الفهرس 
BIPOLAR DISORDEROnly 14 pages are availabe for public view
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Abstract
Bipolar Disorder (BD) is a chronic, debilitating illness with a lifetime worldwide prevalence of 4.8% and more disability-adjusted life-years lost than major neurological conditions or cancer as it causes severe suffering for patients and caregivers, and constitute a major health economic challenge for societies (Gustavsson et al., 2011). According to WHO global burden of disease study, BD rank within the top 20 causes of disability among all medical conditions worldwide, and rank 6th among the mental disorders (Vos et al., 2012).
Patients with bipolar disorder seem to be the most costly in terms of overall medical and psychological care in comparison to other mental patients and one of the most costly categories of patients in the whole field of medicine. (Fountoulakis, 2015)
Although the last few decades, there are available efficacious treatments for Bipolar disorder; often syndromal or symptomatic recovery does not go together with functional recovery. This means that in spite of the fact that patients recover in clinical terms, frequently they do not return to their functioning level as it was before getting ill (Fountoulakis, 2015).
In the clinical setting, many bipolar disorder patients do complain of persistent difficulties in concentration, memory, inability to perform optimally in challenging tasks or even, in day to day functioning. While a variety of factors may be responsible for persistent functional impairments, at least subgroups of patients are likely to experience poor psychosocial outcomes as a result of cognitive dysfunction (Aran et al., 2004; Vaidya et al., 1998 (.
Several studies indicate that as many as 60% of BD patients are cognitively impaired at a level deemed to be clinically relevant during periods of affective remission (Martino et al., 2008 (
Euthymic bipolar disorder patients show limitations in a number of cognitive domains especially executive functions, declarative memory, and sustained attention .This seems to be a cause for a continuous impairment in social and occupational functioning in a large number of patients (Delgado et al., 2012).
Neurocognitive symptoms are not only important because they tell us about the brain areas and functions involved in the pathogenesis of the disease and represent potential endophenotypes, but also for their clinical value; there is an ongoing debate on to what extent they should be included in the diagnostic criteria for schizophrenia and bipolar disorder (Delgado et al., 2012).
Despite being a common and significant illness, the neurophysiologic basis of BD was relatively little studied until the advent of advanced neuroimaging techniques, primarily magnetic resonance imaging tech¬nologies, allowed in vivo non invasive examination of the human brain. Consequently, neuroimaging studies of BD prolif-erated in the past decade (Savetz et al., 2013).
Evaluating white matter of the brain (WM) structure appears to be a promising area of investigation for understanding the potential for altered connectivity between brain regions believed to contribute to bipolar disorder symptomatology. White matter alterations may be responsible for some of the functional activation deficits found in patients with bipolar disorder. Several hypotheses regarding WM abnormalities in bipolar disorder have been suggested (Mahon et al., 2010; Benedetti et al., 2011).
In the last 15 years, there have been major advances in the structural brain imaging of the white matter owing to the development of diffusion tensor imaging MRI. DTI allows both WM microstructure (local organization) and macrostructure (brain anatomical connectivity based on tracts) to be imaged. DTI can detect abnormalities of the WM due to fiber orientation, even when macrostructural changes are absent. DTI has made it possible to study the WM connecting the parts of the brain network involved in emotion regulation and cognitive dysfunctions, supposedly implicated in BD pathophysiology (Marlinge et al., 2014).
For the bipolar I patients in remission, significant decreases in FA were found in the right thalamus, right subgenual anterior cingulate cortex, right inferior frontal area, and left rostral anterior cingulate cortex, compared to the controls (Liu et al., 2010).
Important intrahemispheric WM bundles in the frontotemporal neural circuitry include the uncinate fasciculus (UF) and the cingulum bundle (CB); both carry major connections between the amygdale and vPFC and thus are WM structures especially implicated in BD (Sonja et al., 2014).
Studies have suggested that genes involved in cytoarchitecture of frontotemporal WM structures might be associated with an increased risk of BD (Kim and Webster, 2010).
White matter hyperintensities and MRI WM alterations have been proposed as trait biomarkers of bipolar disorder (Houenou et al., 2012, Hasler et al., 2006) and are observed at the onset of the disorder or in adolescent patients (Pillai et al., 2002, Kafantaris et al., 2009, Rosso et al., 2007). They are of pathophysiological significance in BD as they are associated with a poor clinical and functional outcome (Bearden et al., 2010, Moore et al., 2001, Regenold et al., 2008) and with cognitive decline (Bearden et al., 2001).
Studies in at-risk subjects have suggested that white matter abnormalities of the inferior longitudinal fasciculus and superior longitudinal fasciculus may be endophenotypes of bipolar disorder (Chaddock et al., 2009; Frazier et al., 2007).
Brain regions with significantly decreased FA indices found in the bipolar I patients majorly relate to the cognitive functions. The anterior cingulate cortex is highly involved in the network regulating both cognitive and emotional processing. Particularly, the rostral area locates in the cognitive division of anterior cingulate (Bush et al., 2000) and plays an important role in monitoring/ signaling conflict or interference, decision making, and response to errors (Kelly et al., 2009).
The mean fraction anisotropy value of the right subgenual anterior cingulate cortex was significantly correlated with the scores of short-delayed recall and the mean FA value of the right inferior frontal area was significantly correlated with the performance of perseverative errors, perseverative responses, and word-list recognition (Liu et al., 2010).
The main findings in our study:
In our study we covered two main important areas in euthymic bipolar I patients in comparison with control:
1- Cognitive impairment.
2- White matter abnormalities.
Also in our study we covered three important correlations in bipolar I patients:
1- Correlation between clinical charecteristics of patients with cognitive functions and white matter abnormalities.
2- Correlation of white matter abnormalities with cognitive functions.
I- Comparison between bipolar I group and control group
• Our control group was well match to bipolar group regarding socio demographic characteristics (age, sex, education, marital status) except for occupation as most of case group were unemployed.
• There was statistically significant lower total IQ scores in bipolar group than control group
• As regard cognitive function we found statistically significant poor performance of bipolar I group on all domains of cognitive tests we used in our study (Wechsler memory scale, Wisconsin card sorting test, continuous performance test and trail making test part A and B).
• As regard Diffusion Tensor Image findings we found statistically significant lower Fractional Anisotropy (FA) in bipolar I patients than control group which reflect poor integrity of the white matter in (left rostral anterior cingulate area, right inferior frontal area, bilateral superior longitudinal fascicule, bilateral inferior longitudinal fascicule, bilateral uncinate fascicule and left cingulum in bipolar patients.
II- Correlation of clinical characteristics with cognitive functions in bipolar I patients we found:
• Both average duration of illness and total number of episodes was positively correlated with total omissions of continuous performance test that reflect impaired sustained attention with increased duration of illness.
• Total number of hospitalizations was correlated positively with Wechsler memory test (attention).
• Patients with past history of psychotic features obtained lower scores in Wisconsin card sorting test (conceptual level) than patients without past history of psychotic features.
III- Correlation of clinical characteristics with DTI findings in bipolar I patients we found:
• Average duration of illness and total number of episodes was correlated negatively with FA of right and left longitudinal fasciculus.
• Number of hospitalizations was positively correlated with FA of right uncinate fasciculus.
IV- Correlation of Diffusion Tensor Imaging findings with cognitive functions
• Left rostral anterior cingulated area FA was positively correlated with performance IQ, total IQ, verbal memory, visual memory, general memory, and recall and negatively correlated with total omission errors and Trail making test part B.
• Right inferior frontal area FA was positively correlated with performance IQ and verbal memory and negatively correlated with total omission errors.
• Right superior longitudinal fasciculus FA was positively correlated with performance IQ and verbal memory and negatively correlated with total omission error and Trail making test part B.
• Left superior longitudinal fasciculus FA was positively correlated with verbal IQ, performance IQ, total IQ, verbal memory, general memory and recall and negatively correlated with preservative errors.
• Right inferior longitudinal fasciculus FA was positively correlated with visual memory.
• Left inferior longitudinal fasciculus FA was positively correlated with general memory and negatively correlated with total omission errors.
• Right cingulum FA was positively correlated with verbal memory.
• Left cingulum FA was positively correlated with verbal memory and negatively correlated with trail making part B.
• Right uncinate fasciculus FA was positively correlated with verbal IQ, performance IQ, total IQ, general memory, attention and recall and negatively correlated with preservative errors and trail making test part B.
• Left uncinate fasciculus was positively correlated with verbal IQ, performance IQ and total IQ.
We have done regression analysis between each of (left rostral anterior cingulate, right superior longitudinal fasciculus, left superior longitudinal fasciculus and right uncinate fasciculus) and Wisconsin card sorting test, trail making test part A a nd B and Continous performance test. We found tht CPT omission errors highly statistically significant affecting right superior longitudinal fasciculus in bipolar patients.
Finally our results confirm our hypothesis as we found white matter abnormalities in euthymic bipolar patients correlated with cognitive function which also impaired in this group of patients.
The relationships between neuroimaging and neurocognitive abnormaities in bipolar disorder are worthy of additional investigation. Clearly effort directed twords phenotyping neuropsychiatric disorders using such measures, in addition to other clinical, neuroimaging, neurophysiologic and genotypic information may yield important insight into the development, nature and course of illness. It is hoped that this understanding will lead to better identification of individuals who may be prone to greater cognitive impairment or decline and those who might be more responsive to specific treatment.