**1. Introduction**

262 Neuroimaging – Cognitive and Clinical Neuroscience

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BD is a prevalent mood disorder, often comorbid with other medical and psychiatric conditions and frequently misdiagnosed (Altamura et al., 2011a). Intense emotional states that occur in BD comprise manic, hypomanic, mixed or depressive episodes. According to the Diagnostic and Statistical Manual of Mental Disorders, IVth edition, text revision (DSM-IV–TR; American Psychiatric Association, 2000), BD spectrum ranges from cyclothymia to Bipolar I, Bipolar II Disorder and Not Otherwise Specified (NOS) forms. BD can also be conceptualized as a gradual change in mood scale, which ranges from severe depression to severe mania with an intermediate euthymic state or balanced mood.

Dysthymia is a chronic state of mild low mood occurring for a minimum of two years. At the other end of the scale there is hypomania and severe mania. An alternative and broader dimensional approach conceptualizes BD as a continuum, between unipolar depression, schizoaffective disorder (which is considered by some authors a subcategory of BD) and schizophrenia. This theory may be supported from a clinical point of view by the fact that, sometimes, during severe manic, mixed or depressive episodes, bipolar patients experience psychotic symptoms, such as hallucinations or delusions. It is also supported by the presence of morphometric alterations of frequent observation among major psychoses, such as enlarged ventricles and white matter volume reductions in the left and temporoparietal regions (Czobor et al., 2007).

In BD, symptomatic states are frequently associated with poor working functioning and social impairment. Bipolar patients, moreover, have higher suicide rates than the general population and among the highest of psychiatric patients. In a recent study on factors predicting suicide in BD, white race, family history of suicide, and previous cocaine abuse were considered predictive of suicidal behaviour (Cassidy, 2011). Usually BD develops in early adulthood/late teens, with an age of onset ranging from 15 to 50 years (Cassano et al., 2006).

International treatment guidelines for BD recommend the use of mood stabilizers - either in monotherapy or in association - as the gold standard in both acute and long-term therapy. The concept of stabilization, in fact, has been stressed as the ultimate objective of the treatment of BD, given the chronic and recurrent nature of the illness, which accounts for its significant levels of impairment and disability (Altamura et al., 2011b). Beyond the

Neuroimaging Data in Bipolar Disorder: An Updated View 265

contrasts can be used to improve the visualization of certain normal or abnormal structures

The measurement of total brain volume and ventricular volumes has been the aim of the first investigations using CT in psychiatric disorders. In this perspective, less consistent results have been found for affective disorders compared to schizophrenia and dementia (Beyer et al., 2002). The limited number of controlled CT studies focused on bipolar patients, in fact, showed heterogeneous findings. These include increased lateral ventricle size compared to controls (Andreasen et al., 1990; Nasrallah et al., 1982; Pearlson et al., 1984) or, in contrast, non significant differences between patients and controls (Dewan et al., 1988; Schlegel et al., 1987; Young et al., 1999). A larger third ventricle has been reported as well (Dewan et al., 1988; Schlegel et al., 1987). Studies on cortical alterations in BD revealed that there was no significant difference between patients and controls with respect to the level of cortical atrophy (Iacono et al., 1988; Rieder et al., 1983; Schlegel et al., 1987). However, a positive correlation between increased cortical sulcal widening and age of onset/age of first manic episode has been observed in bipolar patients in a subsequent study (Young et al., 1999). Volumetric changes in the cerebellum have been also reported, including higher rates of atrophy in bipolar patients (Nasrallah et al., 1982), even though the research of these

In synthesis, some studies using CT in bipolar patients found an increased lateral ventricles size. In addition, cortical atrophy (which was not statistically different from controls),

MRI takes advantage of the magnetic properties of the atomic constituents of the tissues in order to create an image of the different parts of the body. Every MRI scanner has a static magnet; its strength usually ranges from 1.5 to 3 Tesla. A steady magnetic field is generated as an electric current passes through the coils. In order to have a nuclear magnetic resonance signal, only atomic nuclei with unpaired protons and/or neutrons can be used. Medical MRI uses essentially hydrogen (¹H) as it is widely diffused in the human body and it has only one proton in its nucleus. Each proton has its own magnetic field or dipole moment, induced by the rotation around its axis. When an externally magnetic field is applied, protons' magnetic dipoles tend to align and to oscillate around the longitudinal axis of the

An horizontal radio frequency (RF) pulse is applied perpendicularly to the longitudinal axis of the external magnetic field with the aim to create a transverse component to the magnetization vector. This induces the generation of an electric current which is transduced into an MRI image. T1 is the "longitudinal" relaxation time and it indicates the time required to regain longitudinal magnetization following RF pulse. T2 is the "transverse" relaxation time that measures how long the resonating protons precess "in phase" following a 90° RF pulse. Due to the T1 and T2 relaxation properties in MRI, differentiation between

Despite intensive research, to date no pathognomonic structural MRI finding has been correlated with affective disorders in general and to BD in particular. There are many heterogeneous data (Table 1) revealing a variety of structural alterations in bipolar patients (Dougherty et al., 2004). It must be considered, moreover, that some of these differences may be referred to the effects of medications (Van der Schot, 2009). For instance, chronic lithium treatment may prevent volume loss in treated patients because of its neuroprotective action

atrophy in the cerebellum as well as a larger third ventricle have also been reported.

applied field (this phenomenon is called precession) (Dougherty et al., 2004).

various tissues in the body is possible (Jezzard et al., 2001).

(Dougherty et al., 2004).

abnormalities is limited.

**2.2 Magnetic Resonance Imaging (MRI)** 

aforementioned core mood symptoms and clinical features of BD, over the last decade, neurocognitive dysfunction has been stressed as another nuclear dimension of BD and, possibly, a marker of its underlying pathophysiology (Lewandowski et al., 2010). There is accumulating evidence that individuals with BD have neurocognitive impairment that persists even during euthymia: the degree of impairment is more severe in patients with depressive symptoms, with functions associated with processing speed and attentional control being particularly implicated (Chaves et al., 2011; Van der Werf-Eldering et al., 2010). In addition, in older euthimic adults with BD, resting-state corticolimbic dysregulation was related to sustained attention deficits and inhibitory control, which could reflect the cumulative impact of repeated affective episodes upon cerebral metabolism and neurocognitive performance (Brooks et al., 2011). Cognitive impairment in BD is influenced by the severity of illness (Yates et al., 2010).

In addition, neuropsychological and imaging studies in BD suggested the presence of cognitive deficits and subtle magnetic resonance imaging (MRI) changes in limbic areas that may persist over euthymia. However, other studies are inconsistent with this claim. For example, a recent study did not identify any difference between BD patients and controls in levels of cognition over a two-year period, indicating that BD doesn't have a significant adverse impact on cognition (Delaloye et al., 2011).

Neuroimaging has recently gained an important role both in clinical practice and research of psychiatric disorders, including BD. Structural imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have contributed to a deeper understanding of the structural changes in the brain in the context of psychiatric disorders. Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI) are techniques which measure changes in response to cognitive demand and/or connectivity between brain regions. As such, these approaches provide an opportunity for investigating the neural bases of behavioural and cognitive impairment in psychiatric populations, including BD.
