Brain Structural And Functional Abnormalities And Drug Treatment Effects In Young Patients With Bipolar Disorder

Objective:Bipolar Disorder(BD)is a serious mental disorder which characterized by abnormalities in patients’mood,attention,energy,and cognitive abilities.Episodic mood dysregulation and cognitive dysfunctions such as attention deficits are the main clinical features of BD.During puberty,the brain regions which responsible for higher-level cognitive functions undergo dramatic changes.The disease may affect the normal neurodevelopmental process.However,the neurobiological mechanism of BD is still unclarified,and the diagnosis of BD mainly depends on the subjective feelings of the patients and the clinical experience of the psychiatrists.Most prior imaging studies only focused on adult patients and exclude the young adolescents and children,but more and more evidences have shown that various factors may affect the neuroimaging characters of BD such as the long illness duration,medication treatment,and substance abuses.Compared with adult patients,younger patients are closer to the onset of the disease and are less exposed to these confounding factors mentioned before.Considering the issues talked above,we would like to explore the core neuropathological mechanism of BD in a group of pediatric and adolescent patients using structural and functional magnetic resonance methods.Psychological medications are the most reliable and effective method for clinical treatment of BD.However,the treatment mechanisms of the psychological medications are also far from being clarified,especially in vivo.Lithium,the classic mood stabilizer,and quetiapine,a second-generation antipsychotic,are two widely used first-line medications treating BD.Prior clinical studies found no overall significant differences in efficacy and safety/tolerability between lithium and quetiapine.Therefore,we combined the cross-sectional case control study and longitudinal clinical trial to explore the brain functional and structural abnormalities in young BD patients at the neuroimage level and explored the lithium and quetiapine’s treatment effects on these abnormalities.Materials and Methods:We recruited 63 healthy age-and sex-matched subjects and 109 young BD I patients.All of them were in manic or mixed phases.We used the Washington University in St.Louis Kiddie Schedule of Affective Disorders and Schizophrenia(WASH-U-KSADS)for BD type I diagnosis and to determine the comorbidities of psychosis and attention deficit hyperactivity disorder.We used the Young Mania Rating Scale to assess the severity of manic symptoms;used the Children’s Depression Rating Scale-Revised to assess the severity of the depressive symptoms;used the Clinical Global Impressions-Severity to assess the overall severity of clinical symptoms.We used a 4 Tesla Varian Unity INOVA magnetic resonance scanner to collect high-definition three-dimensional structural magnetic resonance images from all participants and manually checked the image qualities.The task-based functional magnetic resonance images were gained when participants performing the continuous attention task(CPT-IP).When all patients completed the baseline clinical information and magnetic resonance images’collection,the Cincinnati Children’s Hospital assigned them into two treatment cohorts(lithium and quetiapine)psychiatric research physicians according to their clinical characteristics for 6 weeks’medication treatment.We evaluated the cross-sectional case-control brain structural and functional differences between BD patients and healthy controls in three aspects:regional gray matter morphology,gray matter covariant network and functional connection under cognitive tasks.We also evaluated the longitudinal changes’differences of gray matter network topological and functional connectivity between healthy subjects and patients.(1)For local gray matter morphology,we used Free Surfer(version 6.0.0)to preprocess all the structural magnetic resonances images.We used Desikan template to extract the cortical thickness and subcortical gray matter volume for group-wise comparisons.(2)For the gray matter covariant network,we used the automatic anatomical labeling template to parcellate the brain gray matter into 90 anatomical regions and used the morphological similarities to characterize the gray matter connections which resulted a 90×90 gray matter covariant similarity matrix for each participant.We calculated the topological properties of the brain gray matter network,including small-world parameters,network efficiency parameters,and three types of topological node centralities.(3)For functional connectivity under cognitive tasks,we used SPM12 and SPM-based Conn Toolbox 2018b to preprocess structural and functional magnetic resonance data.We use weighted seed-based connectivity analysis to calculate the functional connection strength under specific task conditions.Results:In terms of the local gray matter morphological features,we found that compared with healthy controls,the cortical thickness of the left inferior frontal gyrus and the left superior lobule cortex in adolescent BD patients were significantly reduced.The volumes of subcortical structures including bilateral thalamus,bilateral putamen,left caudate nucleus and right amygdala in BD group were also significantly reduced compared with the healthy controls.Age and gender have the similar effects on patients and healthy controls.The tobacco,alcohol,and marijuana usage in last 90 days did not have a significant effect on the detected morphological abnormalities.However,if BD patients accompanied by a diagnosis of attention deficit hyperactivity disorder or psychosis,they would like to show more serious structural damage compared with those patients who didn’t.In terms of the gray matter network features,we found that before drug treatment,the clustering coefficients(C_p)and characterized path length(L_p)were increased in young BD patients.We also observed the topological centralities of multiple nodes changed in the patients compared with healthy controls including the right inferior frontal gyrus,bilateral supplementary motor areas,bilateral insula,right parahippocampal gyrus,right superior parietal lobule,and left paracentral lobule.After one-week treatment,the BD patient group still showed increased C_p compared with the healthy control group.However,after six-week treatment,the global network measures between the BD patient and the control group had no significant differences anymore.For nodal topological centralities,the differences between the patients and healthy controls can still be found after one-week treatment,while the number of abnormal nodes was reduced compared to baseline.After six-week treatment,compared with the healthy controls,we only found significant nodal differences in the right inferior frontal gyrus and the left supplementary motor areas.Our random-effect models showed that C_p,L_p,nodal efficiency and degree in the right insula showed significant group-by-time interactions,showing the normalizing effects of the drug treatment.In terms of the functional connectivity measures,we found young bipolar patients had abnormal FC patterns in the emotion and attention related network compared with healthy controls when performing CPT-IP tasks before treatment.Compared to healthy controls,we found the FC between left ventrolateral prefrontal lobe and left temporal pole,the FC between left orbital frontal lobe and right postcentral gyrus and FC between right amygdala and right occipital poles were increased in untreated young bipolar patients and the FC between the ventrolateral prefrontal lobe and bilateral anterior cingulate gyrus and FC between left insula and bilateral anterior cingulate gyrus were decreased.After one-week treatment,we found that compared with healthy subjects,patients in the quetiapine but not in the lithium treatment group showed decreased FC between left ventrolateral prefrontal lobe and left temporal pole and FC between left orbital frontal lobe and right postcentral gyrus towards to the normal level.After six-week treatment,even though we didn’t find any differences of treatment effects in terms of FC changes between quetiapine and lithium treatment group,we found that the FC between the left insula and the bilateral anterior cingulate gyrus showed a significant group-by-time interaction effect comparing the whole patients’sample with the healthy subjects.Conclusions:The results of current study suggested that before receiving medication treatment,young BD patients showed obvious abnormalities in regional brain gray matter morphology,gray matter network and task-based FC properties compared to healthy subjects.These abnormalities were mainly in brain areas or brain networks supporting attention and emotion regulation.Some clinical symptoms,such as mania,are also closely related to these abnormal imaging features.After a 6-week lithium or quetiapine drug treatment,we found that under the intervention of drug treatment;the abnormalities found before treatment gradually disappeared.Our results showed the therapeutic effects of the psychotic medications were not only reflected in the improvement of clinical symptoms but also can be reflected in neuroimaging properties.But notably,we only found limited evidence to support that lithium and quetiapine have significant differences in altering brain structure and function.Together,the longitudinal changes of the brain structures and functions after medication treatment also suggest that the neuropathological differences between adult and young BD patients may partly because of the influence of drug treatment.Pediatric and adolescent BD patients who are much closer to the initial stage of the disease and are less confounded by other factors such as drug treatment may provide more unique and useful information about the essence of the neuropathology properties of BD.