Abnormalities In Mood Disorders Research Articles

138. Biomarkers of Reward and Avoidance Neural Circuitry Abnormalities in Mood Disorders and OCD: Toward New Neural Targets for Neuromodulation Interventions

Abnormally elevated left ventrolateral prefrontal cortical (vlPFC)-ventral striatal (VS) activity during uncertain reward and outcome expectancy characterizes Bipolar Disorder (BD) and high impulsive sensation seeking. Persistent avoidance and abnormal orbitofrontal cortex (OFC) activity during avoidance acquisition characterize OCD. We are determining if these neural biomarkers are targets for neuromodulation for BD and OCD.

The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder

Here, we review a novel concept namely the compensatory immune-regulatory reflex system (CIRS) as applied to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). There is evidence that a substantial subset of individuals with MDD and BD exhibit an activation of the immune-inflammatory response system (IRS), as indicated by an increased production of macrophagic M1 and T helper (Th)-1 pro-inflammatory cytokines, interleukin (IL)-6 trans-signaling, positive acute phase proteins (APPs), and complement factors. These immune aberrations appear to be evident during the course of major affective episodes of either depressive or (hypo) manic polarity. Here, we review (a) the current state of the art of CIRS functions in both mood disorders and (b) the possible role of CIRS-related biomarkers for the understanding of affective disorders within the framework of precision psychiatry that could also provide novel drug targets for both MDD and BD. CIRS-related abnormalities in mood disorders include elevated Th-2 and T regulatory (Treg) activities with increased IL-4 and IL-10 production, classical IL-6 signaling, increased levels of sIL-1R antagonist (sIL-1RA), soluble IL-2 (sIL-2R) and tumor necrosis factor-α- receptors, and positive APPs, including haptoglobin, hemopexin, α1-acid glycoprotein, α1-antitrypsin, and ceruloplasmin. It is concluded that CIRS is involved in MDD and BD by regulating the primary immune-inflammatory response, thereby contributing to spontaneous and antidepressant-promoted recovery from the acute phase of illness. Signs of activated IRS and CIRS pathways are observed in the remitted phases of both disorders indicating that there is no return to the original homeostasis after an acute episode, while later episodes of mood disorders are characterized by sensitized IRS and CIRS responses. New z-unit weighted composite biomarker scores are proposed, which reflect different aspects of IRS versus CIRS activation and may be used to estimate different IRS/CIRS activity ratios in mood and other neuroimmune disorders.

Effect of desipramine and fluoxetine on energy metabolism of cerebral mitochondria

Brain bioenergetic abnormalities in mood disorders were detected by neuroimaging in vivo studies in humans. Because of the increasing importance of mitochondrial pathogenetic hypothesis of Depression, in this study the effects of sub-chronic treatment (21days) with desipramine (15mg/kg) and fluoxetine (10mg/kg) were evaluated on brain energy metabolism. On mitochondria in vivo located in neuronal soma (somatic) and on mitochondria of synapses (synaptic), the catalytic activities of regulatory enzymes of mitochondrial energy-yielding metabolic pathways were assayed.Antidepressants in vivo treatment modified the activities of selected enzymes of different mitochondria, leading to metabolic modifications in the energy metabolism of brain cortex: (a) the enhancement of cytochrome oxidase activity on somatic mitochondria; (b) the decrease of malate, succinate dehydrogenase and glutamate-pyruvate transaminase activities of synaptic mitochondria; (c) the selective effect of fluoxetine on enzymes related to glutamate metabolism.These results overcome the conflicting data so far obtained with antidepressants on brain energy metabolism, because the enzymatic analyses were made on mitochondria with diversified neuronal in vivo localization, i.e. on somatic and synaptic. This research is the first investigation on the pharmacodynamics of antidepressants studied at subcellular level, in the perspective of (i) assessing the role of energy metabolism of cerebral mitochondria in animal models of mood disorders, and (ii) highlighting new therapeutical strategies for antidepressants targeting brain bioenergetics.

Glial abnormalities in mood disorders.

Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders. These findings suggest that the proliferation and survival of glial cells may be important in the pathogenesis of mood disorders and may be possible targets for the development of new treatments. In this article we review the evidence for glial abnormalities in mood disorders, and we discuss glial cell biology and evidence from postmortem studies of mood disorders. The goal is not to carry out a comprehensive review but to selectively discuss existing evidence in support of an argument for the role of glial cells in mood disorders.

Disturbance of the glutamatergic system in mood disorders.

The role of glutamatergic system in the neurobiology of mood disorders draws increasing attention, as disturbance of this system is consistently implicated in mood disorders including major depressive disorder and bipolar disorder. Thus, the glutamate hypothesis of mood disorders is expected to complement and improve the prevailing monoamine hypothesis, and may indicate novel therapeutic targets. Since the contribution of astrocytes is found to be crucial not only in the modulation of the glutamatergic system but also in the maintenance of brain energy metabolism, alterations in the astrocytic function and neuroenergetic environment are suggested as the potential neurobiological underpinnings of mood disorders. In the present review, the evidence of glutamatergic abnormalities in mood disorders based on postmortem and magnetic resonance spectroscopy (MRS) studies is presented, and disrupted energy metabolism involving astrocytic dysfunction is proposed as the underlying mechanism linking altered energy metabolism, perturbations in the glutamatergic system, and pathogenesis of mood disorders.

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities

Depressed patients show evidence of both proinflammatory changes and neurophysiological abnormalities such as increased amygdala reactivity and volumetric decreases of the hippocampus and ventromedial prefrontal cortex (vmPFC). However, very little is known about the relationship between inflammation and neuroimaging abnormalities in mood disorders. A whole genome expression analysis of peripheral blood mononuclear cells yielded 12 protein-coding genes (ADM, APBB3, CD160, CFD, CITED2, CTSZ, IER5, NFKBIZ, NR4A2, NUCKS1, SERTAD1, TNF) that were differentially expressed between 29 unmedicated depressed patients with a mood disorder (8 bipolar disorder, 21 major depressive disorder) and 24 healthy controls (HCs). Several of these genes have been implicated in neurological disorders and/or apoptosis. Ingenuity Pathway Analysis yielded two genes networks, one centered around TNF with NFKβ, TGFβ, and ERK as connecting hubs, and the second network indicating cell cycle and/or kinase signaling anomalies. fMRI scanning was conducted using a backward-masking task in which subjects were presented with emotionally-valenced faces. Compared with HCs, the depressed subjects displayed a greater hemodynamic response in the right amygdala, left hippocampus, and the ventromedial prefrontal cortex to masked sad versus happy faces. The mRNA levels of several genes were significantly correlated with the hemodynamic response of the amygdala, vmPFC and hippocampus to masked sad versus happy faces. Differentially-expressed transcripts were significantly correlated with thickness of the left subgenual ACC, and volume of the hippocampus and caudate. Our results raise the possibility that molecular-level immune dysfunction can be mapped onto macro-level neuroimaging abnormalities, potentially elucidating a mechanism by which inflammation leads to depression.

Circadian rhythms: strong evidence on how to approach depression

It is widely accepted that mood disorders are related to biological rhythm abnormalities. It has been proved that this happens at least in a significant proportion of patients which profit from chronotherapeutic interventions. Rhythm abnormalities in mood disorders include among others diurnal mood variation, elevated nocturnal body temperature, lower nocturnal TSH, overall increased cortisol secretion, phase advance of cortisol and melatonin secration and sleep architecture abnormalities. The exact relationship of these abnormalities to the etiopathogenesis of depression remains unclear; it is however evident that at least some treatment modalities worsen rhythms, leave residual symptoms and therefore do not lead to full remission, which sould be the ultimate goal of any treatment approach. It seems important for an informed approach and understanding of mood disorders and their treatment to take into consideration the normalization and stabilization of endogenous rhythms.

Morningness–eveningness and depression: Preliminary evidence for the role of the behavioral activation system and positive affect

There is considerable evidence of circadian rhythm abnormalities in mood disorders. Morningness–eveningness, the degree to which people prefer organizing their activity and sleep patterns toward the morning or evening, is related to circadian phase and is associated with mood, with relatively greater psychological distress among evening types. Given that circadian rhythms may also relate to the Behavioral Activation System (BAS) and positive affect (PA), but not to the Behavioral Inhibition System (BIS) or negative affect (NA), it was hypothesized that individual differences in BAS sensitivity and levels of PA, but not BIS and NA, would explain the association between morningness–eveningness and depression in a sample of 208 individuals with a range of depressive symptomatology. As predicted, increasing eveningness was associated with greater depression, lower BAS, and lower PA, but not directly associated with NA. Path analyses supported a model wherein morningness–eveningness is associated with depression via multi-step indirect paths including BAS-Reward Responsiveness, PA, and NA. A path between BIS and depression was distinct from the one involving morningness–eveningness. A variety of alternative path models all provided a weaker fit to the data. Thus, results were consistent with the BAS and PA mediating the effects of morningness–eveningness on depression.

Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.

The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger “default system” of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression

Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression

Within-Session Mood Changes From TMS in Depressed Patients

Within-Session Mood Changes From TMS in Depressed Patients

Within-Session Mood Changes From TMS in Depressed Patients

Transcranial magnetic stimulation has become an increasingly well studied tool in neuropsychiatry. It has been applied in neurophysiology and as a treatment modality in various neurological and psychiatric disorders. Regarding the treatment of major depressive disorder, several meta-analyses of a number of randomized sham-controlled trials using repetitive transcranial magnetic stimulation (TMS), 1–6 have produced a significant body of evidence supporting its efficacy. Target areas of repetitive TMS in the treatment of mood disorders are the left and the right prefrontal cortex. The selection of these areas is based on evidence from neuroimaging and neuropsychological studies that suggest that prefrontal cortical areas show significant abnormalities in mood disorders. 7–10 During treatment with TMS, magnetic pulses are applied to the scalp. These pulses induce an electrical current in the underlying cortical tissue which results in depolarization of cortical neurons. Indirectly TMS also has effects on related cortical and subcortical areas as evidenced by studies of the motor cortex. 11,12 TMS studies regarding mood disorders have focused largely on depressed patients during a course of TMS, which usually consists of multiple treatment sessions conducted over several weeks. In contrast, studies regarding immediate effects of TMS on mood and on neural networks have mostly assessed healthy subjects. Reasons for studying healthy subjects rather than depressed patients include concerns about symptom heterogeneity in depression and the impact of psychotropic medications. 13,14

Reciprocal Effects of Antidepressant Treatment on Activity and Connectivity of the Mood Regulating Circuit: An fMRI Study

Reciprocal Effects of Antidepressant Treatment on Activity and Connectivity of the Mood Regulating Circuit: An fMRI Study

Distribution of Serotonin Transporter Labeled Fibers in Amygdaloid Subregions: Implications for Mood Disorders

The serotonin transporter 5-HTT mediates responses to serotonin reuptake inhibitors (SSRIs), a mainstay treatment in mood disorders. The amygdala, a key emotional processing center, has functional abnormalities in mood disorders, which resolve following successful SSRI treatment. To better understand the effects of SSRIs in mood disorders, we examined the distribution of 5-HTT labeled fibers relative to specific nuclear groups in the amygdala. Immunocytochemical techniques were used to chart 5-HTT labeled fibers in the amygdala in coronal sections through the brain of six adult Macaques. Nissl staining was used to define nuclear groups in the amygdala. The serotonin transporter 5-HTT is distributed heterogeneously in the primate amygdala, with the lateral subdivision of the central nucleus, intercalated cell islands, amygdalohippocampal area, and the paralaminar nucleus showing the heaviest concentrations. 5HTT-labeled fibers are very densely concentrated in output regions of the amygdala. High concentrations of 5-HTT-positive fibers in the central nucleus indicate that tight regulation of serotonin is critical in modulating fear responses mediated by this nucleus. High concentrations of 5-HTT-labeled fibers in the intercalated islands and parvicellular basal nucleus/paralaminar nucleus, which contain immature -appearing neurons, suggest a potential trophic role for serotonin in these subregions.

Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania

The processing of facial emotion involves a distributed network of limbic and paralimbic brain structures. Many of these regions are also implicated in the pathophysiology of mood disorders. Behavioural data indicate that depressed subjects show a state-related positive recognition bias for faces displaying negative emotions. There are sparse data to suggest there may be an analogous, state-related negative recognition bias for negative emotions in mania. We used functional magnetic resonance imaging (fMRI) to investigate the behavioural and neurocognitive correlates of happy and sad facial affect recognition in patients with mania. Functional MRI and an explicit facial affect recognition task were used in a case-control design to measure brain activation and associated behavioural response to variable intensity of sad and happy facial expressions in 10 patients with bipolar I mania and 12 healthy comparison subjects. The patients with mania had attenuated subjective rating of the intensity of sad facial expressions, and associated attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, with increased activation in the posterior cingulate and posterior insula. No behavioural or neurocognitive abnormalities were found in response to presentation of happy facial expressions. Patients with mania showed a specific, mood-congruent, negative bias in sad facial affect recognition, which was associated with an abnormal profile of brain activation in paralimbic regions implicated in affect recognition and mood disorders. Functional imaging of facial emotion recognition may be a useful probe of cortical and subcortical abnormalities in mood disorders.

Neuroplasticity in mood disorders

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.

Applications of positron emission tomography in psychiatry

Blood flow, metabolism, and structural imaging studies suggest altered neural circuits in major psychiatric disorders including mood disorders, schizophrenia, and obsessive compulsive disorder. Neuroreceptor mapping studies have identified serotonergic abnormalities in mood disorders and dopaminergic abnormalities in schizophrenia. Further imaging applications have involved development of new positron emission tomgraphy (PET) tracers that may identify abnormalities in peptide neurotransmitter systems such as corticotrophin releasing factor or substance P. Finally, PET can play an important role in quantifying the relationship between receptor occupancy, drug blood levels, oral dose and therapeutic outcome. In that way PET scanning can contribute to both therapeutics and to drug development by more rapid identification of the likely therapeutic dose range compared with conventional parallel group dose comparisons or dose ranging studies.

Neuroanatomical studies on bipolar disorder

Background Neuroimaging data showing structural and functional brain abnormalities in mood disorders suggest that brain alterations at the neurohistological level may underlie the macropathology seen by imaging in vivo. Aims To summarise recent post-mortem studies on affective disorders, with a focus on bipolar disorder. Method Literature review and discussion of results from volumetric, cyto-architectural and immunohistochemical analyses. Results Basal ganglia are smaller in patients with depression irrespective of diagnostic polarity. In addition, higher neuron numbers have been reported in the locus caeruleus of patients with bipolar disorder compared with those with unipolar depression. Patients with bipolar as well as unipolar illness show subtle structural deficits in the dorsal raphe. Histological data are consistent with a regional reduction in the synthesis of noradrenalin and serotonin, which appears to be compensated by antidepressants. Conclusion Preliminary results suggest that, aside from functional dysregulation, subtle structural abnormalities in the brain may contribute to the pathogenesis of mood disorders.

Subgenual prefrontal cortex abnormalities in mood disorders.

Pathological disturbances of mood may follow a 'bipolar' course, in which normal moods alternate with both depression and mania, or a 'unipolar' course, in which only depression occurs. Both bipolar and unipolar disorders can be heritable illnesses associated with neurochemical, neuroendocrine and autonomic abnormalities. The neurobiological basis for these abnormalities has not been established. Using positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, we have now localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives. This decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as magnetic resonance imaging (MRI) demonstrated reductions in the mean grey matter volume in the same area of 39 and 48% in the bipolar and unipolar samples, respectively. This region has previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs.