Functional neuroimaging in mood disorders

PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS

Functional neuroimaging in mood disorders

Mood disorders (DSM-IV)

Sophia Frangou

Depressive disorders

Bipolar disorders

Major Depressive Episode (MDE)

Bipolar Disorder I (BDI)

Dysthymic Disorder

Bipolar Disorder II (BDII)

Major Depressive Disorder (MDD)

Cyclothymic Disorder

Source: American Psychiatric Association, 1994.1

The hallmark of mood disorders is episodic pathological changes in emotional state, which are associated with abnormalities in cognition and behaviour. At present, mood disorders are divided into major depressive disorder (MDD) characterized by recurrent depressive episodes and bipolar affective disorder (BD), where episodes of depression are interspersed with periods of mania (Type I BD; BDI) or hypomania (Type II BD; BDII) (Figure 1).1 Mood disorders are associated with significant psychosocial disability and rank among the 30 leading causes of the global burden of disease. Several brain regions are involved in emotional processing and in the integration of emotion with cognition and visceral functions (Figure 2). These include the prefrontal cortex (PFC), the anterior cingulate cortex (ACC), the amygdala, the parahippocampal gyrus and the hippocampus. These regions are heavily interconnected and also connected with other brain structures, particularly the thalamus, hypothalamus and striatum. Our understanding of the neural circuitry involved in mood disorders is rapidly expanding through the ever-increasing application of functional brain imaging techniques. Such techniques include positron emission tomography (PET) or single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI). Compared with other techniques, fMRI offers superior temporal and spatial resolution, which allows a more accurate examination of the neural networks associated with cognitive processes. A selective review of functional neuroimaging studies in patients with primary mood disorders was undertaken in order to identify points of commonality and controversy in the existing literature.

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ity and depressive symptoms. They conducted a factor analysis of the symptoms of 40 MDD patients; the anxiety-related factor correlated positively with CBF in the posterior cingulate cortex and inferior parietal lobule bilaterally, the psychomotor retardation/depressed mood related factor correlated negatively with CBF in the DLPFC cortex and angular gyrus, both on the left. The third and final factor related to cognitive performance and correlated positively with CBF in the left medial PFC.10 Resting state studies, with few exceptions (e.g. Tutus et al.9), have not found differences in the pattern or degree of brain activity changes between MDD and BD patients when depressed. Brain activation studies: acutely depressed patients showed reduced activation in the PFC during a verbal fluency task.11 Two studies have examined the pattern of brain activation in response to the N-back sequential verbal memory task, which allows for the parametric manipulation of working memory load. Barch et al. found that compared with controls, moderately depressed MDD patients showed reduced activation in the thalamus bilaterally, and the precentral gyrus and parietal cortex on the right.12 In contrast, Harvey and colleagues found greater activation of the lateral PFC and the anterior cingulate in depressed MDD patients compared to healthy subjects despite comparable task performance.13

Brain regions involved in emotional processing Prefrontal cortex

Depressive states Resting state studies (Figure 3) 18 F-fluorodeoxyglucose (FDG) PET studies of acutely depressed BD and/or unipolar (UP) patients have demonstrated glucose metabolism to be reduced in frontal relative to posterior brain regions2 and increased in the amygdala and anterior cingulate.3–5 Studies that measured cerebral blood flow (CBF) using 99m Tc-hexamethylpropyleneamine oxime (HMPAO) or 133Xe SPECT have also reported reductions in CBF in frontal regions but also in temporal and limic/paralimbic structures.6–9 Bench et al. conducted the most detailed examination of correlations between brain activ-

Cingulate cortex

Amygdala/Hippocampus

Sophia Frangou MSc PhD is Reader in Psychiatry at the Institute of Psychiatry, London, UK, where she heads the Section of the Neurobiology of Psychosis. Her research interests include neuroimaging and the pathophysiology of bipolar disorder and schizophrenia.

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Thalamus

Hypothalamus

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while positive picture–caption pairs resulted in increased activation in the inferior frontal gyrus on the left and the parahippocampal gyrus, subgenual cingulate and striatum on the right. Using a similar paradigm, Mahli et al.18 reported additional activation in the amygdala, thalamus, hypothalamus and medial globus pallidus in depressed BD patients compared to controls.

Brain activity in depressive states

Manic states Resting state studies (Figure 4) Brain activity during manic states has been found to be reduced within ventral PFC areas19–21 but increased in the ACC (mostly in left dorsal regions) and basal ganglia.22 Precuneus Paracentral lobule

Brain activation studies: Blumberg et al.,23 using 15O-H2O PET, found that when performing a verbal fluency task manic subjects had decreased right rostral and orbital PFC activation compared to controls. Using a picture–caption pair paradigm Malhi et al.24 compared hypomanic BD patients with healthy subjects. In addition to changes in activation in the frontal and cingulate gyri found in previous studies, they also observed additional increased activation in the thalamus and caudate in patients.

Lingual Cuneus

Cingulate gyrus Superior frontal gyrus

BA

Septal region A. Paraterminal gyrus B. Subcallosal area Increased activity Decreased activity

Remission Two studies that compared remitted BD patients to controls with respect to regional CBF during a verbal fluency task found no group differences.23,25 Patients as well as controls showed reduced activity in the superior temporal cortex bilaterally and negative co-variation between CBF in left prefrontal and right (but not left) temporal regions. Curtis et al.26 largely confirmed and extended these findings. They compared remitted BD patients to controls (and schizophrenics) using fMRI. BD patients performed similarly to controls and their pattern of brain activation observed was also comparable. There were differences, however, in the degree of activation, which was greater in BD patients in superior parietal and frontal regions. Blumberg and colleagues27 used the colour–word Stroop task to compare manic, depressive and remitted BD patients with controls. The pattern of brain activation was similar across all groups but there were differences in signal intensity. Blunted response in the ventral PFC was noted in the right side in manic patients and on the left in patients with depression. However, reduced activation relative to controls was seen in all patient groups, regardless of affective state, in the left rostral VPFC – a region that corresponds approximately to BA 10 and 47. Monks et al.28 used the 2-back condition of the N-back task and the Sternberg paradigm (which also allows parametric manipulation of working memory load) to compare euthymic male BD patients to age- and gender-matched controls. In the 2-back condition, BD patients showed reduced activation in frontal, parietal and temporal regions bilaterally whilst activation in the left precentral, right medial frontal and left supramarginal gyri was increased. However, no group differences were found in the Sternberg task, even at increased memory load. Finally, Frangou29 examined the pattern of brain activation of remitted BD patients to controls matched for age, gender and cognitive function. Group differences were observed only in response to increasing memory load, whereas the predicted dynamic response in the dorsal PFC was absent in patients who showed increased activation in the parietal cortices and middle frontal gyrus instead.

Hippocampal formation Entorhinal part of parahippocampal gyrus Amygdaloid nucleus

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Several studies have explored the neural correlates of emotional processing using different versions of the facial affect discrimination task. In this paradigm, subjects are shown human faces expressing different affective states, which can be neutral, happy, sad or angry. Yurgelun-Todd et al. used this paradigm to compare brain activation to fearful and happy expressions in BD patients and controls. They found that in response to fearful facial affect patients showed reduced activation in the DLPFC and increased in the amygdala.14 Using a similar paradigm, Surguladze et al.15 and Keedwell et al.16 compared depressed MDD patients to controls. Patients showed increased activation in response to sad faces in the left amygdala/parahippocampal gyrus15 and in the ventromedial PFC.16 The magnitude of activation in limbic regions correlated with the severity of depression,15 while in controls increased activation in the PFC was associated with happy and not sad faces.16 Emotional processing has also been examined in fMRI studies using the picture–caption pairs paradigm that informs about neural responses based on the meaning or the interpretation of emotionally valenced pictures. Kumari et al.17 found that compared to controls, treatment-resistant MDD patients had decreased activation in the right ACC when viewing both negative and positive picture–caption pairs and in the left medial frontal gyrus and hippocampus when presented with positive picture–caption pairs. In addition, patients showed increased activation to negative picture–caption pairs in the right inferior and left middle temporal gyri

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PFC activation is reduced and/or spreads to a wider network of regions as if more cortical resources are needed in order sustain task performance. There is some evidence that most of the functional changes reported here are state-related. To date, trait-related deficits have been reported mostly in the PFC, particularly in ventral regions, while dorsal PFC dysfunction is subtle and becomes apparent under conditions of increased mental load or effort. Such trait-related abnormalities have been reported mostly in remitted BD rather than MDD patients. The degree of convergence across studies despite the variety of methodological approaches used allows optimism about the validity of the evidence to date. However, there are many factors that may confound our view of the pathophysiological mechanisms involved in primary mood disorders. The most important consideration is that of the effect of medication (and possibly other types of treatment) on brain function and structure. A growing body of evidence from several lines of research suggests that chronic antidepressants and lithium administration may result in MR visible morphological and functional changes.30–32 The mechanisms are unclear, although the possibility of neurotrophic/neuroprotective effects of medication has been suggested.30 An additional consideration is the potential of medication to alter the magnitude of the blood oxygenation level dependent (BOLD) signal in fMRI via mechanisms unrelated to the disease process. Silverstone et al.33 reported that healthy controls and remitted but not depressed BD patients showed a decrease in BOLD signal in Broca’s area, the left pre-central gyrus, and the supplemental motor area during a verbal fluency task after 14 days of lithium treatment. These results highlight the complexity of interactions between disease, symptomatic status, medication and activation paradigms and emphasize the need for increased sophistication in our study design and data interpretation. Other potential sources of variability are the presence of co-morbid conditions such as anxiety or substance abuse. Despite limitations, evidence from functional imaging studies has allowed us to make significant progress in our knowledge of the neural circuitry involved in mood disorders. Future studies should focus on the examination of state-related abnormalities in mania, further investigation of trait-related deficits in euthymic patients, and clarification of the effects of medication on the BOLD signal. 

Brain activity in manic states

Precuneus Paracentral lobule

Lingual Cuneus

Cingulate gyrus Superior frontal gyrus

BA

Septal region A. Paraterminal gyrus B. Subcallosal area Increased activity Decreased activity

Hippocampal formation Entorhinal part of parahippocampal gyrus Amygdaloid nucleus

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Discussion The studies reviewed suggest that PFC dysfunction may be a key feature of affective disorders while increased activation or activity in limbic regions such as the ACC, amygdala, striatum, thalamus and insula is more often associated with depressive states. There is much less information about brain activity during manic states, although existing data suggest that ventral PFC dysfunction is present. The precise direction and the interpretation of these brain functional changes is still a matter of debate. Studies that measured CBF or glucose metabolism have reported decreased activity during depressive episodes, particularly within dorsal but also ventral PFC regions. In contrast, fMRI studies that measure brain activation have reported increases in the PFC of depressed patients when viewing negative compared to neutral affective stimuli. PFC regions in general exert a regulatory and mostly inhibitory influence on subcortical structures. A possible explanation for the observed increase in PFC activation is that it represents a compensatory reaction in these regulatory cortical regions in response to the increased activation within the limbic system. However, the decreased PFC activity seen in PET and SPECT studies suggests that the functional integrity of the PFC may be compromised. Further support for this has been provided by fMRI evidence from studies using emotionally neutral paradigms. Such studies have found that PSYCHIATRY 5:5

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