Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder?

The authors reviewed magnetic resonance imaging volumetric imaging results in major mood disorders, particularly comparing similarities and differences from studies of bipolar disorder and unipolar major depression. Abnormalities of cerebral brain regions appear inconsistently in mood disorders and, when present, typically consist of decreased frontal or prefrontal cortical volumes in both unipolar depression and bipolar disorder. In contrast, subcortical and medial temporal abnormalities are more commonly observed and are different between these two major classes of affective illness. Specifically, whereas structural enlargement of the basal ganglia and amygdala have been observed in bipolar disorder, in unipolar depression, these structures appear to be smaller in patients than healthy subjects. These findings suggest that affective illnesses may share in common an underdeveloped or atrophied prefrontal region, leading to loss of cortical modulation of limbic emotional networks. The effect of this loss results in unipolar depression or cycling (mania with depression) depending on the abnormalities of the subcortical structures involved. The cerebellum may also play a role in the presentation of mood disorders. This hypothesis remains speculative as much more research is needed to specifically examine how morphometric brain abnormalities translate into the neurophysiologic deficits that produce mood disorders.     

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.     

Physiopathology of bipolar disorders: what have changed in the last 10 years?

Despite recent efforts to understand the neurobiology of Bipolar Disorder (BD), the exact pathophysiology remains undetermined. Due to the effects of various psychopharmacological agents, initial research focused on the study of biogenic amines. Recent evidence has shown that dysfunction in intracellular signaling systems and gene expression may be associated with BD. These alterations may cause interruptions in mood regulating circuits such as the limbic system, striatum and prefrontal cortex, and the neuroprotective effects of mood stabilizers may reverse this pathological process. This study aims to update the recent findings relative to the neurochemistry of BD.     

Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.

BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.     

Fronto-limbic circuitry in euthymic bipolar disorder: evidence for prefrontal hyperactivation

Functional magnetic resonance imaging (fMRI) studies of bipolar disorder have revealed fronto-limbic abnormalities in patients during manic and depressive episodes. However, relatively few studies have examined neural activity during euthymia, leaving unanswered questions concerning the impact of mood state on activity in these brain regions. In the present study, we examined 15 remitted bipolar type I patients and 16 demographically matched healthy comparison subjects during performance on an affective face-matching task previously shown to elicit amygdala hyperactivation and prefrontal hypoactivation in manic relative to healthy subjects. In our euthymic sample, amygdala activation did not differ from controls. However, bipolar patients showed hyperactivation in inferior prefrontal cortical regions compared with controls, a finding that contrasts with the hypoactivation previously reported in this region in manic patients. Given the reciprocal relationship between the prefrontal cortex and limbic structures, we propose state-related amygdala activity, similar to that of healthy controls, may be associated with prefrontal hyperactivation when bipolar patients are asymptomatic.     

Elevated neuron number in the limbic thalamus in major depression

OBJECTIVE: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders. METHOD: Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain. RESULTS: There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects. CONCLUSIONS: The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.     

Signaling: cellular insights into the pathophysiology of bipolar disorder.

Clinical studies over the years have provided evidence that monoamine signaling and hypothalamic-pituitary-adrenal axis disruption are integral to the pathophysiology of bipolar disorder. A full understanding of the pathophysiology from a molecular to a systems level must await the identification of the susceptibility and protective genes driving the underlying neurobiology of bipolar disorder. Furthermore, the complexity of the unique biology of this affective disorder, which includes the predisposition to episodic and often progressive mood disturbance, and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our progress to date. Imaging studies in patient populations have provided evidence of a role for anterior cingulate, amygdala, and prefrontal cortex in the pathophysiology of bipolar disorder. More recent research strategies designed to uncover the molecular mechanisms underlying our pharmacologic treatments and their interaction in the regulation of signal transduction as well as more advanced brain imaging studies remain promising approaches. This experimental strategy provides data derived from the physiologic response of the system in affected individuals and addresses the critical dynamic interaction with pharmacologic agents that effectively modify the clinical expression of the pathophysiology.     

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.     

What can neuroimaging findings tell us about sleep disorders?

Models of the pathophysiology of human sleep disorders have only recently been tested using nuclear medicine assessments, which have greatly increased our understanding of the brain mechanisms involved in the human sleep-wake cycle. Dramatic changes in function have been observed in large-scale neuronal networks during sleep. Broad declines in heteromodal-association-cortical function, and relative increases in limbic and paralimbic function have been observed. These cortical areas are responsible for essential aspects of human behavior, allowing us to interact with the world around us and to evaluate the significance of important events in our lives. Preliminary findings suggest that fundamental alterations in the function of these neural systems occur in sleep disorders. In depression, alterations in rapid-eye-movement and slow-wave sleep appear linked to a sleep-related dysfunctional arousal in primary limbic and paralimbic structures (amygdala), and hypofunction in frontal cortical areas. Pharmacologic interventions partially reverse these alterations. Preliminary studies in insomia indicate a subcortical hyperarousal and a failure of sleep to provide normal restoration of function in the prefrontal cortex, leading to chronic sleep deprivation. This review discusses functional neuroimaging data on normal sleep, and on the pathophysiology of insomnia related to depression and primary insomnia.     

Prolonged hemodynamic response during incidental facial emotion processing in inter-episode bipolar I disorder

This fMRI study examined whether hemodynamic responses to affectively-salient stimuli were abnormally prolonged in remitted bipolar disorder, possibly representing a novel illness biomarker. A group of 18 DSM-IV bipolar I-diagnosed adults in remission and a demographically-matched control group performed an event-related fMRI gender-discrimination task in which face stimuli had task-irrelevant neutral, happy or angry expressions designed to elicit incidental emotional processing. Participants’ brain activation was modeled using a “fully informed” SPM5 basis set. Mixed-model ANOVA tested for diagnostic group differences in BOLD response amplitude and shape within brain regions-of-interest selected from ALE meta-analysis of previous comparable fMRI studies. Bipolar-diagnosed patients had a generally longer duration and/or later-peaking hemodynamic response in amygdala and numerous prefrontal cortex brain regions. Data are consistent with existing models of bipolar limbic hyperactivity, but the prolonged frontolimbic response more precisely details abnormalities recognized in previous studies. Prolonged hemodynamic responses were unrelated to stimulus type, task performance, or degree of residual mood symptoms, suggesting an important novel trait vulnerability brain dysfunction in bipolar disorder. Bipolar patients also failed to engage pregenual cingulate and left orbitofrontal cortex—regions important to models of automatic emotion regulation—while engaging a delayed dorsolateral prefrontal cortex response not seen in controls. These results raise questions about whether there are meaningful relationships between bipolar dysfunction of specific ventromedial prefrontal cortex regions believed to automatically regulate emotional reactions and the prolonged responses in more lateral aspects of prefrontal cortex.     

Functional neuroimaging of visceral sensation.

The use of functional brain imaging techniques has led to considerable advances in our understanding of brain processing of human visceral sensation. The use of complementary techniques such as functional MRI, positron emission tomography, magnetoencephalography, and EEG has led to the identification of a network of brain areas that process visceral sensation. These studies suggest that unlike somatic sensation, which has an intense homuncular representation in the primary somatosensory cortex (SI), visceral sensation is primarily represented in the secondary somatosensory cortex, whereas representation in SI is vague. This difference could account for the poor localization of visceral sensation in comparison with somatic sensation. However, in a manner similar to that of somatic sensation, visceral sensation is represented in the paralimbic and limbic structures such as the insular, anterior cingulate, and prefrontal cortices. These areas are likely to mediate the affective and cognitive components of visceral sensation. Recent studies suggest that negative emotional factors such as fear, and cognitive factors such as attention can modulate the brain processing of visceral sensation in the insular and anterior cingulate cortices. In addition, alterations in the pattern of cortical processing of visceral sensation have been described in patients with functional gastrointestinal pain. It is likely that future research into the factors that modulate the brain processing of visceral sensation in health and disease are likely to improve further our understanding of the pathophysiology of functional visceral pain disorders.     

Brain‐derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain‐derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant‐naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant‐naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.     

Cell pathology in mood disorders

In new, exciting, neuroanatomic studies on postmortem tissues from patients with mood disorders, quantitative cytomorphologic differences can be shown at the microscopic level. These investigations provide direct evidence that mood disorders are characterized by marked reductions in glial cell number and density in addition to subtle alterations in the density and size of cortical neurons in frontolimbic brain regions. Importantly, this corresponds with clinical neuroimaging studies and preclinical animal studies that suggest cell atrophy, cell loss, or impairments in neuroplasticity and cellular resilience may underlie the neurobiology of major depressive disorder and bipolar manic-depressive disorder. Because this represents a departure from modern efforts to understand mood disorders, published reports are scarce and based on rather small sample sizes. This article reviews the current findings from postmortem studies on glial and neuronal cell counts in primary mood disorders and discusses a possible link between cellular changes and the action of psychotherapeutic drugs.     

Predictors of treatment response in bipolar disorders: evidence from clinical and brain imaging studies

The clinical features of bipolar disorders can be correlated with responses to medications. Patients who respond to lithium, for example, often present differently from those who respond to divalproex or carbamazepine, but the correlations are relatively modest. Brain-imaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), can relate brain function to clinical features and medication responses. For example, in depression, it appears that prefrontal cortical function is decreased while subcortical anterior paralimbic activity is increased. Preliminary evidence suggests that baseline metabolism increases and decreases in the left insula may be associated with carbamazepine and nimodipine responses, respectively, and that cerebral lithium concentrations may correlate with antimanic effects. Although it is not yet a clinical tool for bipolar disorders, brain imaging provides useful research data to understand the fundamental neurobiology of mood disorders and to more effectively target therapeutics.     

Mood disorders following traumatic brain injury

Mood disorders are a frequent complication of traumatic brain injury that exerts a deleterious effect on the recovery process and psychosocial outcome of brain injured patients. Prior psychiatric history and impaired social support have been consistently reported as risk factors for developing mood disorders after traumatic brain injury (TBI). In addition, biological factors such as the involvement of the prefrontal cortex and probably other limbic and paralimbic structures may play a significant role in the complex pathophysiology of these disorders. Preliminary studies have suggested that selective serotonin reuptake inhibitors such as sertraline, mood stabilizers such as sodium valproate, as well as stimulants and ECT may be useful in treating these disorders. Mood disorders occurring after TBI are clearly an area of neuropsychiatry in which further research in etiology as well as treatment is needed.     

Mood disorders following traumatic brain injury

Mood disorders are a frequent complication of traumatic brain injury that exerts a deleterious effect on the recovery process and psychosocial outcome of brain injured patients. Prior psychiatric history and impaired social support have been consistently reported as risk factors for developing mood disorders after traumatic brain injury (TBI). In addition, biological factors such as the involvement of the prefrontal cortex and probably other limbic and paralimbic structures may play a significant role in the complex pathophysiology of these disorders. Preliminary studies have suggested that selective serotonin reuptake inhibitors such as sertraline, mood stabilizers such as sodium valproate, as well as stimulants and ECT may be useful in treating these disorders. Mood disorders occurring after TBI are clearly an area of neuropsychiatry in which further research in etiology as well as treatment is needed.     

Cognitive neuroscience and brain imaging in bipolar disorder

Bipolar disorder is characterized by a combination of state-related changes in psychological function that are restricted to illness episodes, coupled with trait-related changes that persist through periods of remission, irrespective of symptom status. This article reviews studies that have investigated the brain systems involved in these state- and trait-related changes, using two techniques: (i) indirect measures of neurocognitive function, and (ii) direct neuroimaging measures of brain function during performance of a cognitive task. Studies of neurocognitive function in bipolar disorder indicate deficits in three core domains: attention, executive function, and emotional processing. Functional imaging studies implicate pathophysiology in distributed neural circuitry that includes the prefrontal and anterior cingulate cortices, as well as subcortical limbic structures including the amygdala and the ventral striatum. Whilst there have been clear advances in our understanding of brain changes in bipolar disorder, there are limited data in bipolar depression, and there is limited understanding of the influence of clinical variables including medication status, illness severity, and specific symptom dimensions.     

Can brain-imaging studies provide a 'mood stabilizer signature?'

Brain-imaging investigations have attempted to characterize the neurobiological basis of bipolar disorder. Preliminary studies have also focused on in vivo brain correlates of treatment response with antidepressants, mood stabilizers and other psychotropic medications. A MEDLINE literature search was conducted dating back to 1966. Selected in vivo brain-imaging studies that examined neurobiological correlates of treatment response in mood disorder patients were identified. Discrete anatomical abnormalities in subregions of the prefrontal cortex, medial temporal lobe and cerebellum have been identified in bipolar patients. Functional imaging studies suggested abnormalities in particular brain circuits encompassing these same brain regions and the striatum. However, functional imaging correlates of treatment response with lithium or other mood stabilizers have not yet been characterized. Neurochemical studies suggested a reduction in N-acetyl aspartate levels in prefrontal cortex and abnormalities in membrane phospholipids in frontal and temporal lobes. Preliminary findings suggest that lithium may increase the gray matter content and N-acetyl aspartate levels in various cortical regions, which could reflect its putative neurotrophic effects. Few in vivo receptor-imaging studies have examined brain correlates of treatment response in bipolar patients. The available studies suggest anatomical, neurochemical and functional brain abnormalities in bipolar patients. However, in vivo brain correlates of treatment response with mood stabilizers in bipolar patients have not yet been well characterized.     

Cellular plasticity and resilience and the pathophysiology of severe mood disorders

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.     

Amygdalar excitatory/inhibitory circuits interacting with orexinergic neurons influence differentially feeding behaviors in hamsters

Schizophrenia (SCZ) and bipolar disorder (BP) are associated with neuropathological brain changes, which are believed to disrupt connectivity between brain processes and may have common properties. Patients at first psychotic episode are unique, as one can assess brain alterations at illness inception, when many confounders are reduced or absent.SCZ (N = 25) and BP (N = 24) patients were recruited in a regional first episode psychosis MRI study. VBM methods were used to study gray matter (GM) and white matter (WM) differences between patient groups and case by case matched controls.For both groups, deficits identified are more discrete than those typically reported in later stages of illness. SCZ patients showed some evidence of GM loss in cortical areas but most notable were in limbic structures such as hippocampus, thalamus and striatum and cerebellum. Consistent with disturbed neural connectivity WM alterations were also observed in limbic structures, the corpus callosum and many subgyral and sublobar regions in the parietal, temporal and frontal lobes. BP patients displayed less evidence of volume changes overall, compared to normal healthy participants, but those changes observed were primarily in WM areas which overlapped with regions identified in SCZ, including thalamus and cerebellum and subgyral and sublobar sites.At first episode of psychosis there is evidence of a neuroanatomical overlap between SCZ and BP with respect to brain structural changes, consistent with disturbed neural connectivity. There are also important differences however in that SCZ displays more extensive structural alteration.