Biology of bipolar disorder

577:. Prefrontal abnormalities are less consistently reported, although hyperactivation in the ventral prefrontal cortex is a fairly consistent finding. Hyperactivity in the amygdala and hypoactivity in the medial and ventral prefrontal cortex during exposure to emotional stimuli has been interpreted as reflecting dysfunction in emotional regulation circuits. Increased effective connectivity between the amygdala and orbitofrontal cortex, and elevated striatal responsiveness during reward tasks have been interpreted as hyper-responsiveness in positive emotion and reward circuitry. The abnormal activity in these circuits has been observed in non-emotional tasks, and is congruent with changes in grey and white matter in these circuits. Neural response during reward tasks differentiates unipolar depression from bipolar depression, with the former being associated with reduced neural response and the latter being associated with elevated neural response. An ALE meta analysis of functional neuroimaging comparing adults and adolescents found a larger degree of hyperactivity in the inferior frontal gyrus and precuneus, as well as a larger degree of hypoactivity in the anterior cingulate cortex in adolescents relative to adults 477:

dorsolateral prefrontal cortex, and cerebellar vermis. Structural imaging studies frequently find abnormalities in these regions which are putatively involved in emotional and cognitive functions that are disrupted in bipolar disorder. For example, while structural neuroimaging studies do not always find abnormal PFC volume in bipolar disorder, when they do, PFC volume is reduced. Furthermore, reduced PFC volume is associated with response inhibition deficits and duration of illness. When the PFC at large is not examined and the focus is narrowed to the orbitofrontal cortex and medial prefrontal cortex, results more consistently observed reductions, although not in bipolar youth. The sgACC volume is observed to be reduced not only in bipolar disorder, but also in unipolar disorder, as well as people with a family history of affective disorders. Enlargement of the striatum and globus pallidus are commonly found, and although some studies fail to observe this, at least one study has reported no volumetric but subtle morphometric abnormalities.

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blood flow in the sgACC that normalizes with treatment. Congruent with these abnormalities is a reduction in glial cells observed in post mortem studies, and reduced integrity of white matter possibly involving a hemispheric imbalance. Findings in the rACC are largely the same as the sgACC (reduced GM, increased metabolism), although more studies have been carried out on protein expression and neuronal morphology. The rACC demonstrates reduced expression NMDA, kainate and GABA related proteins. These findings may be compensating for increased glutaminergic afferents, evidenced by increased Glx in MRS studies. One VBM study reported reduced grey matter in the dACC. Inconsistent results have been found during functional neuroimaging of cognitive tasks, with both decreased and increased activation being observed. Decreased neuron volume and a congruent increase in neural density have been found in the dACC. Reduced expression of markers of neural connectivity have been reported (e.g.

372:, excess baseline activity could result in null findings due to subtraction analysis. Furthermore, heterogenous study design could mask consistent hyperactivity to specific stimuli. Regardless of directionality of amygdala abnormalities, as the amygdala plays a central role in emotional systems, these findings support dysfunctional emotional circuits in bipolar. A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. The dorsal ACC is commonly under-activated in bipolar, and is generally implicated in cognitive functions, while the ventral ACC is hyperactive and implicated in emotional functions. Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder. Strakowski, along with DelBello and Adler have put forward a model of 562:

limbic metabolism and reduced ACC metabolism. Mania is also associated with dlPFC and OFC hypometabolism. Limbic hypermetabolism is more consistent than in bipolar depression, but the overall study quality is low due to limitations associated with neuroimaging in acutely manic patients. Another review reported that mania is generally associated with frontal/ventral hypoactivation, while depression is generally associated with the opposite. A degree of lateralization with regard to abnormalities has been reported, with mania being associated with the right hemisphere, and depression the left. Trait abnormalities in euthymic patients have been observed, including hypoactivity in the ventral prefrontal cortex, and hyperactivity in the amygdala.

534:, left rostral middle frontal cortex, right inferior parietal cortex, along with an increase in the right entorhinal cortex. Duration of illness was associated with reductions bilaterally in the pericalcarine gyrus, left rostral anterior cingulate and right cuneus, along with increases in the right entorhinal cortex. Treatment with lithium was associated with increased cortical thickness bilaterally in the superior parietal gyrus, left paracentral gyrus, and left paracentral lobule. A history of psychosis was associated with reduced surface area in the right frontal pole. Another study on subcortical abnormalities by the same research group reported reductions in the hippocampus, amygdala, and thalamus, along with ventricular enlargement. 605:

reduced activity was reported bilaterally in the inferior frontal gyrus. Compared to major depressive disorder, bipolar patients overactivated the vACC, pulvinar nucleus, and parahippocampus gyrus/amygdala to a greater degree, while underactivating the dACC. Bipolar subjects overactivated parahippocampus for both fearful and happy expressions, while the caudate and putamen were overactive for happiness and fear respectively. Bipolar subjects also underactivated the ACC for both fearful and happy expressions, while the IFG was underactivated for fearful expressions only. These results were interpreted as reflecting increased engagement with emotionally salient stimuli in bipolar disorder.

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Investigation of Bipolar, Endophenotypes.; Sprooten, E; Glahn, DC; Pearlson, GD; Emsell, L; Kenney, J; Scanlon, C; McDonald, C; Cannon, DM; Almeida, J; Versace, A; Caseras, X; Lawrence, NS; Phillips, ML; Dima, D; Delvecchio, G; Frangou, S; Satterthwaite, TD; Wolf, D; Houenou, J; Henry, C; Malt, UF; Bøen, E; Elvsåshagen, T; Young, AH; Lloyd, AJ; Goodwin, GM; Mackay, CE; Bourne, C; Bilderbeck, A; Abramovic, L; Boks, MP; van Haren, NE; Ophoff, RA; Kahn, RS; Bauer, M; Pfennig, A; Alda, M; Hajek, T; Mwangi, B; Soares, JC; Nickson, T; Dimitrova, R; Sussmann, JE; Hagenaars, S; Whalley, HC; McIntosh, AM; Thompson, PM; Andreassen, OA (December 2016).

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this fact. "The polygenic common rare variant" hypothesis suggests that a large number of risk conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The "multiple rare variant" model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease. The familial transmission of mania and depression are largely independent of each other. This raises the possibility that bipolar is actually two biologically distinct but highly comorbid conditions.

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to stimulation of olfactory neurons is also observed. These findings are congruent with the genetic association of bipolar with CACNAC1, an L-type calcium channel, as well as the efficacy of anti-epileptic agents. Normal platelets placed in plasma from people with bipolar disorder do not demonstrate elevated levels of intracellular calcium, indicating that dysfunction lies intracellularly. One possible mechanism is that elevated inositol triphosphate (IP3) caused by hyperactive neuronal calcium sensor 1 causes excessive calcium release. Serum levels of

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are fairly consistent. Structurally, secondary mania is associated with destructive lesions that tend to occur in the right hemisphere, particularly the frontal cortex, mesial temporal lobe and basal ganglia. Functionally hyperactivity in the left basal ganglia and subcortical structures, and hypoactivity in the right ventral prefrontal and basotemporal cortex have been reported in cases of secondary mania. The destruction of right hemisphere or frontal areas is hypothesized to lead to a shift to excessive left sided or subcortical reward processing.

255:" of mood disorders suggests that major environmental stressors trigger initial mood episodes, but as mood episodes occur, weaker and weaker triggers can precipitate an affective episode. This model was initially created for epilepsy, to explain why weaker and weaker electrical stimulation was necessary to elicit a seizure as the disease progressed. While parallels have been drawn between bipolar disorder and epilepsy, supporting the kindling hypothesis, this model is generally not supported by studies directly assessing it in bipolar subjects. 1530:

Bauer, M; Hautzinger, M; Moebus, S; Priebe, L; Czerski, PM; Hauser, J; Lissowska, J; Szeszenia-Dabrowska, N; Brennan, P; McKay, JD; Wright, A; Mitchell, PB; Fullerton, JM; Schofield, PR; Montgomery, GW; Medland, SE; Gordon, SD; Martin, NG; Krasnow, V; Chuchalin, A; Babadjanova, G; Pantelejeva, G; Abramova, LI; Tiganov, AS; Polonikov, A; Khusnutdinova, E; Alda, M; Grof, P; Rouleau, GA; Turecki, G; Laprise, C; Rivas, F; Mayoral, F; Kogevinas, M; Grigoroiu-Serbanescu, M; Propping, P; Becker, T; Rietschel, M; Nöthen, MM; Cichon, S (11 March 2014).

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SB; Fraser, C; Blumenstiel, B; Defelice, M; Breen, G; Gill, M; Morris, DW; Elkin, A; Muir, WJ; McGhee, KA; Williamson, R; MacIntyre, DJ; MacLean, AW; St, CD; Robinson, M; Van Beck, M; Pereira, AC; Kandaswamy, R; McQuillin, A; Collier, DA; Bass, NJ; Young, AH; Lawrence, J; Ferrier, IN; Anjorin, A; Farmer, A; Curtis, D; Scolnick, EM; McGuffin, P; Daly, MJ; Corvin, AP; Holmans, PA; Blackwood, DH; Gurling, HM; Owen, MJ; Purcell, SM; Sklar, P; Craddock, N; Wellcome Trust Case Control, Consortium. (September 2008).

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anti-apoptotic gene expression in both peripheral cells and neurons, as well as the reduction in BDNF that is consistently found in bipolar. Reductions in cortical glia are not found across the whole cortex (e.g. somatosensory areas demonstrate normal glial density and counts), indicating that systematic dysfunction in glial cells is not likely; rather, abnormal functionality of connectivity in specific regions may result in abnormal glia, which may in turn exacerbate dysfunction.

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emotional stimuli having excessive impact on mood. Deficits in working memory associated with abnormal dlPFC function could also translate to impaired ability to represent emotional stimuli, and therefore the impaired ability to reappraise emotional stimuli. Dysfunction in the amygdala and striatum has been associated with attentional biases, and may represent a bottom up mechanism of dysfunctional emotional processing.

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This model was supported by a number of common neuroimaging findings. Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. While amygdala hyperactivity is not a uniform finding, a number of methodological challenges could explain discrepancies. As most studies utilize fMRI to measure

549: 601:. In bipolar depression, reduced activity was reported in the sgACC, ACC, and middle frontal gyrus. In euthymia, reduced activity was reported in the dlPFC, vlPFC, and ACC, while increased activity was reported in the amygdala. During studies examining response to emotional faces, both mania and euthymia were reported to be associated with elevated amygdala activity. 481:

increased risk of cardiovascular disease in bipolar. On the other hand, the observation of reduced white matter integrity in frontal-subcortical regions makes it possible that these hyperintensities play a role dysfunction between limbic and cortical regions. Global brain volume and morphology are normal in bipolar. Regional deficits in volume have been reported in

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In a study by Bschor, Müller-Oerlinghausen, and Ulrich (2001), improvement of manic symptoms occurred about 2 h after oral intake of methylphenidate in a manic patient with signs of unstable EEG-vigilance regulation. Three months later, when the patient was admitted anew, a rapid antimanic effect was again shown after re-exposition to methylphenidate

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wherein limbic abnormalities are present early on, but rostral prefrontal abnormalities develop later in the course. The importance of limbic dysfunction early in development is highlighted by the observation that amygdala lesions early in adulthood produce emotional abnormalities that are not present in people who develop amygdala damage in adulthood.

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regions. Although unipolar depression was associated with reductions in the ventral most and dorsal most regions of the mPFC and bipolar with a region near the genu of the corpus callosum, the overlap was still statistically significant. Similar to the overlap with major depression, a significant overlap of bipolar disorder with

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the pregenual anterior cingulate cortex (BA24) and anterior cingulate cortex (BA32). One meta analysis reported enlargement of the lateral ventricles and globus pallidus, as well as reductions in hippocampus volume and cross sectional area of the corpus callosum. Another meta analysis reported a similar increase volumes of the

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Wise, T; Radua, J; Via, E; Cardoner, N; Abe, O; Adams, TM; Amico, F; Cheng, Y; Cole, JH; de Azevedo Marques Périco, C; Dickstein, DP; Farrow, TFD; Frodl, T; Wagner, G; Gotlib, IH; Gruber, O; Ham, BJ; Job, DE; Kempton, MJ; Kim, MJ; Koolschijn, PCMP; Malhi, GS; Mataix-Cols, D; McIntosh, AM; Nugent, AC;

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Ferreira, MA; O'Donovan, MC; Meng, YA; Jones, IR; Ruderfer, DM; Jones, L; Fan, J; Kirov, G; Perlis, RH; Green, EK; Smoller, JW; Grozeva, D; Stone, J; Nikolov, I; Chambert, K; Hamshere, ML; Nimgaonkar, VL; Moskvina, V; Thase, ME; Caesar, S; Sachs, GS; Franklin, J; Gordon-Smith, K; Ardlie, KG; Gabriel,

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have been reported in bipolar. Levels of some (IL-6 and CRP) but not all (TNFα) may be reduced by treatment. Increases in IL-6 have been reported in mood episodes, regardless of polarity. Inflammation has been consistently reported in bipolar disorder, and the progressive nature lies in dysregulation

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The observation of increased Glx in the prefrontal cortex is congruent with the observation of reduced glial cell counts and prefrontal cortex volume, as glia play an important role in glutamate homeostasis. Although the number and quality of studies examining NMDA receptor subunits is poor, evidence

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hyperactivity, although most evidence for this mechanism is indirect. The gene DGKH has been reported in genome wide association studies to be related to bipolar disorder, and it is known to be involved in PKC regulation. Manipulation of PKC in animals produces behavioral phenotypes similar to mania,

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and OFC during emotional processing, receipt of reward, and anticipation of reward. Increased activity in the striatum and OFC has also been reported in euthymia during anticipation and receipt of reward, although this finding is extremely inconsistent. These abnormalities may be related to circadian

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The phenomenology and neuroanatomy of mania secondary to neurological disorders is consistent with findings in primary mania and bipolar disorder. While the diversity of lesions and difficulty in ruling out premorbid psychiatric conditions limit the conclusions that can be drawn, a number of findings

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mood. The cause and mechanism of bipolar disorder is not yet known, and the study of its biological origins is ongoing. Although no single gene causes the disorder, a number of genes are linked to increase risk of the disorder, and various gene environment interactions may play a role in predisposing

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Hibar, DP; Westlye, LT; van Erp, TG; Rasmussen, J; Leonardo, CD; Faskowitz, J; Haukvik, UK; Hartberg, CB; Doan, NT; Agartz, I; Dale, AM; Gruber, O; Krämer, B; Trost, S; Liberg, B; Abé, C; Ekman, CJ; Ingvar, M; Landén, M; Fears, SC; Freimer, NB; Bearden, CE; Costa Rica/Colombia Consortium for Genetic

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Decreased neuron density and soma size in the ACC and dlPFC has been observed. The dlPFC also demonstrates reduced glial density, a finding that is less consistent in the ACC. The reduction in cell volume may be due to early stage apoptosis, a mechanism that is supported by studies observing reduced

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Calcium homeostasis may be impaired across all mood states. Elevated basal intracellular, and provoked calcium concentrations in platelets and transformed lymphoblasts are found in people with bipolar. Serum concentrations of calcium are also elevated, and abnormal calcium concentrations in response

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with treatment. Another review reported inositol abnormalities in the basal ganglia, and frontal, temporal and cingulate regions. The finding of a trend towards increased NAA concentrations in the dlPFC may be due to medication status, as treatment with lithium or valproate has been noted to lead to

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A 2016 meta analysis reported that bipolar disorder was associated with grey matter reductions bilaterally in the ACC, vmPFC, and insula extending to the temporal lobe. When compared with grey matter reductions in unipolar depression, significant overlap occurred in the insular and medial prefrontal

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In healthy controls, amygdala volume is inversely related to age. This relationship is reversed in bipolar disorder, and meta analyses have found reduced amygdala volume in pediatric bipolar disorder, and increased amygdala volume in adulthood. This is hypothesized to reflect abnormal development of

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Clinically, mania is characterized by spending sprees, poor judgement, and inappropriate speech and behavior. Congruent with this, mania is associated impulsivity on Go-No Go tasks, deficits in emotional decision making, poor probabilistic reasoning, impaired ability on continuous performance tasks,

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Hibar, D P; Westlye, L T; Doan, N T; Jahanshad, N; Cheung, J W; Ching, C R K; Versace, A; Bilderbeck, A C; Uhlmann, A; Mwangi, B; Krämer, B; Overs, B; Hartberg, C B; Abé, C; Dima, D; Grotegerd, D; Sprooten, E; Bøen, E; Jimenez, E; Howells, F M; Delvecchio, G; Temmingh, H; Starke, J; Almeida, J R C;

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In conclusion, stimulants in bipolar disorder seem to be relatively safe, and there are even several case reports suggesting rapid antimanic effects of psychostimulants (Beckmann & Heinemann, 1976; Garvey, Hwang, Teubner-Rhodes, Zander, & Rhem, 1987; Max, Richards, & Hamdanallen, 1995).

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have been inconsistent, although limited evidence points towards reduced central serotonin signaling in a subgroup of aggressive or suicidal patients. Studies assessing the binding potential of the serotonin transporter or serotonin receptors have also been inconsistent, but generally point towards

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Different regions of the ACC have been studied in the literature, with the subgenual (sgACC) and rostral (rACC) parts being largely separated. Grey matter volume in the sgACC has been, albeit with some exceptions, found to be reduced in bipolar. Along with this, bipolar is associated with increased

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A 2010 meta analysis of differences in regional grey matter volume between controls and bipolar disorder reported reductions bilaterally in the inferior frontal cortex and insula, which extended more prominently in the right side to include the precentral gyrus, as well as grey matter reductions in

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Green at al 2007 suggested a model of bipolar disorder based on the convergence of cognitive and emotional processing on certain structures. For example, the dACC and sgACC were cognitively associated with impairment of inhibition of emotional responses and self monitoring, which could translate to

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measured by 8-hydroxy-2'-8-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Levels of 8-OHdG and 8-oxodG are widely used as measures of oxidative stress in mental illnesses. It was determined from this meta-analysis that oxidative DNA damage was significantly increased in

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Chen, DT; Jiang, X; Akula, N; Shugart, YY; Wendland, JR; Steele, CJ; Kassem, L; Park, JH; Chatterjee, N; Jamain, S; Cheng, A; Leboyer, M; Muglia, P; Schulze, TG; Cichon, S; Nöthen, MM; Rietschel, M; BiGS.; McMahon, FJ; Farmer, A; McGuffin, P; Craig, I; Lewis, C; Hosang, G; Cohen-Woods, S; Vincent,

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An activation likelihood estimate meta analysis of bipolar studies that used paradigms involving facial emotions reported a number of increases and decreases in activation compared to healthy controls. Elevated activity was reported in the parahippocampal gyrus, putamen, and pulvinar nuclei, while

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Regardless of mood state, during response inhibition tasks, people with bipolar disorder underactivate the right inferior frontal gyrus. Changes specific on euthymia include hyperactivations in the left superior temporal gyrus and hypoactivations in the basal ganglia, and changes specific to mania

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susceptible to bipolar disorder (i.e., have a number of relatives with bipolar disorder) have produced few consistent results. Consistent abnormalities in adult first degree relatives include larger insular cortex volumes, while offspring demonstrate increased right inferior frontal gyrus volumes.

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and lateral ventricles, as well as increased amygdala volume relative to people with schizophrenia. Reductions have also been reported in the right inferior frontal gyrus, insula, pars triangularis, pars opercularis, and middle and superior temporal gyrus. Structural neuroimaging in people who are

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A model of functional neuroanatomy produced by a workgroup led by Stephen M. Strakowski concluded that bipolar was characterized by reduced connectivity, due to abnormal pruning or development, in the prefrontal-striatal-pallidal-thalamic-limbic network leading to dysregulated emotional responses.

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Charney, AW; Ruderfer, DM; Stahl, EA; Moran, JL; Chambert, K; Belliveau, RA; Forty, L; Gordon-Smith, K; Di Florio, A; Lee, PH; Bromet, EJ; Buckley, PF; Escamilla, MA; Fanous, AH; Fochtmann, LJ; Lehrer, DS; Malaspina, D; Marder, SR; Morley, CP; Nicolini, H; Perkins, DO; Rakofsky, JJ; Rapaport, MH;

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A meta analysis using region of interest (as opposed to statistical parametric mapping) analysis reported abnormalities across paradigms for euthymic, depressed, and manic subjects. In bipolar mania, reduced activity was reported in the superior, middle, and inferior frontal gyri, while increased

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of bipolar is estimated at 79%-93%, and first degree relatives of bipolar probands have a relative risk of developing bipolar around 7–10. While the heritability is very high, no specific genes have been conclusively associated with bipolar, and a number of hypotheses have been posited to explain

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is between 6% and 32%. Corticosteroids may precipitate mania, supporting the role of the HPA axis in affective episodes. Measures from urinary versus salivary cortisol have been contradictory, with one study of the former concluding that HPA hyperactivity was a trait marker, while a study of the

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have been proposed. The biogenic amine hypothesis posits general dysregulation of monoamines underlies bipolar and affective disorders. The cholinergic aminergic balance hypothesis posits that an increased ratio of cholinergic activity relative to adrenergic signaling underlies depression, while

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Studies examining resting blood flow, or metabolism generally observed abnormalities dependent upon mood state. Bipolar depression is generally associated with dlPFC and medial orbitofrontal cortex hypometabolism. Less consistent associations include reduced temporal cortex metabolism, increased

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In a review of structural neuroimaging in bipolar disorder, Strakowski proposed dysfunction in an iterative emotional network called the "anterior limbic network", composed of the thalamus, globus pallidus, striatum, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, ACC, amygdala,

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Delvecchio, G; Fossati, P; Boyer, P; Brambilla, P; Falkai, P; Gruber, O; Hietala, J; Lawrie, SM; Martinot, JL; McIntosh, AM; Meisenzahl, E; Frangou, S (February 2012). "Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: a voxel-based

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Mühleisen, TW; Leber, M; Schulze, TG; Strohmaier, J; Degenhardt, F; Treutlein, J; Mattheisen, M; Forstner, AJ; Schumacher, J; Breuer, R; Meier, S; Herms, S; Hoffmann, P; Lacour, A; Witt, SH; Reif, A; Müller-Myhsok, B; Lucae, S; Maier, W; Schwarz, M; Vedder, H; Kammerer-Ciernioch, J; Pfennig, A;

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signaling cascades in response to stimulation by dopamine receptor D2 or NMDA receptors may be involved in bipolar mania. The evidence for this is primarily pharmacological, based on the observation that drugs that are effective in treating bipolar reduced AA cascade magnitude, while drugs that

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to G proteins has been observed. While linkage studies performed on genes related to G protein signaling, as well as studies on post mortem mRNA concentration fail to report an association with bipolar disorder, the overall evidence suggests abnormal coupling of neurotransmission systems with G

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Hypersensitivity of reward systems is consistent across mood states in bipolar, and is evident in the prodrome. Increases in goal directed behavior, risk taking, positive emotions in response to reward, ambitious goal setting and inflexibility in goal directed behaviors are present in euthymia.

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Blond et al. proposed a model centered on dysfunction in an "amygdala-anterior paralimbic" system. This model was based on the consistent functional and structural abnormalities in the ventral prefrontal cortex and amygdala. The model also proposes a developmental component of bipolar disorder,

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Kishi, T; Yoshimura, R; Fukuo, Y; Kitajima, T; Okochi, T; Matsunaga, S; Inada, T; Kunugi, H; Kato, T; Yoshikawa, T; Ujike, H; Umene-Nakano, W; Nakamura, J; Ozaki, N; Serretti, A; Correll, CU; Iwata, N (November 2011). "The CLOCK gene and mood disorders: a case-control study and meta-analysis".

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Structural neuroimaging studies consistently report increased frequency of white matter hyperintensities in people with bipolar. However, whether or not the lesions play a causative role is unknown. It is possible that they are a result of secondary factors, such as the processes underlying an

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In novel environments, both bipolar manic and bipolar euthymic people demonstrate increased activity, exploration and linear movement that is greater than controls, people with ADHD and people with schizophrenia. Using this behavioral pattern in "reverse translational" studies, this behavioral

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During acute mood episodes, people with bipolar demonstrate mood congruent processing biases. Depressed patients are quicker to react to negatively valenced stimuli, while manic patients are quicker to react to positively valenced stimuli. Acute mood episodes are also associated with congruent

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rhythm dysfunction in bipolar, including increased sleep latency, evening preference and poor sleep quality, as the neural systems responsible for both processes are functionally linked. A few lines of evidence suggest that elevated dopamine signaling, possibly due to reduced functionality in

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using pharmacological or genetic means produces a similar behavioral pattern in animal models. Pharmacological data is consistent with dysfunction of dopamine in bipolar as some studies have reported hypersensitivity to stimulants (however, some studies have found that stimulants effectively

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John O. Brooks III put forward a model of bipolar disorder involving dysregulation of a circuit called the "corticolimbic system". The model was based on more or less consistent observations of reduced activity in the medial orbitofrontal cortex, vlPFC, and dlPFC, as well as the more or less

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are associated with between a 10%-70% risk of affective switch from depression to mania or hypomania, depending upon the criteria used. The more robust association between TCAs and affective switches, as opposed to more selective drugs, has been interpreted as indicating that more extensive

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demonstrate increased rates of bipolar disorder before the onset of CPEO, and the higher rate of maternal inheritance patterns support this hypothesis. Downregulation of genes encoding for mitochondrial subunits, decreased concentration of phosphocreatine, decreased brain pH, and elevated

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Specific symptoms have been linked to various neuroimaging abnormalities in bipolar disorder, as well as schizophrenia. Reality distortion, disorganization, and psychomotor poverty have been linked to prefrontal, thalamic, and striatal regions in both schizophrenia and bipolar (Table 1).

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Medeiros, H; Sobell, JL; Green, EK; Backlund, L; Bergen, SE; Juréus, A; Schalling, M; Lichtenstein, P; Roussos, P; Knowles, JA; Jones, I; Jones, LA; Hultman, CM; Perlis, RH; Purcell, SM; McCarroll, SA; Pato, CN; Pato, MT; Craddock, N; Landén, M; Smoller, JW; Sklar, P (10 January 2017).

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Although the role of acute mood states is unknown, grey matter volume is generally reported as reduced in the dlPFC, along with resting and task evoked functional signals. Signals of myelination and density of GABAegic neurons is also reduced in the dlPFC, particularly in layers II-V.

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link the analogy with epilepsy to a possible reduction in inhibitory activity in emotional circuits. Overlap with epilepsy extends to include abnormalities in intracellular signaling, biochemistry in the hippocampus and prefrontal cortex, and structure and function of the amygdala.

593:, hippocampus, and amygdala. State specific abnormalities were reported for mania and euthymia. During mania, hypoactivation was significant in the inferior frontal gyrus, while euthymia was associated with hypoactivation of the lingual gyrus and hyperactivation of the amygdala. 404:

consistent observations of increased activity in the amygdala, parahippocampal gyrus, cerebellar vermis, anterior temporal cortex, sgACC, and ACC. This pattern of abnormal activity was suggested to contribute to disrupted cognitive and affective processes in bipolar disorder.

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gene have been tested for association, although findings have been inconsistent, and one meta analysis has reported no association with either bipolar or major depressive disorder. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL,

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Belvederi Murri, M; Prestia, D; Mondelli, V; Pariante, C; Patti, S; Olivieri, B; Arzani, C; Masotti, M; Respino, M; Antonioli, M; Vassallo, L; Serafini, G; Perna, G; Pompili, M; Amore, M (January 2016). "The HPA axis in bipolar disorder: Systematic review and meta-analysis".

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abnormalities during decision making tasks. Depressed bipolar is associated with conservative responding, while manic bipolar is associated with liberal responses. Both depression and mania are associated with similar and broad cognitive impairments, including on tests of

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studies demonstrating an association between reduced DAT functionality and manic symptoms. The binding potential of muscarinic receptors are reduced in vivo during depression, as well as in post mortem studies, supporting the cholinergic aminergic balance hypothesis.

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Goh XX, Tang PY, Tee SF. 8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis. Psychiatry Investig. 2021 Jul;18(7):603-618. doi: 10.30773/pi.2020.0417. Epub 2021 Jul 22. PMID 34340273; PMCID:

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increased adrenergic signaling relative to cholinergic signaling underlies mania. The permissive hypothesis suggests that serotonin is necessary but not sufficient for affective symptoms, and that reduced serotonergic tone is common to both depression and mania.

839:'s binding potential has been observed to be decreased. Drugs that release dopamine produce effects similar to mania, leading some to hypothesize that mania involves increased catecholaminergic signalling. Dopamine has also been implicated through genetic 920:

latter concluded that no difference in HPA activity exists in remission. Measurement during the morning are thought to be more sensitive due to the cortisol awakening response. Studies are generally more consistent, and observe HPA hyperactivity.

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Due to the inconsistent findings in GWAS, multiple studies have undertaken the approach of analyzing SNPs in biological pathways. Signaling pathways traditionally associated with bipolar disorder that have been supported by these studies include

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One particular SNP located on CACNA1C that confers risk for bipolar disorder is also associated with elevated CACNA1C mRNA expression in the prefrontal cortex, and increased calcium channel expression in neurons made from patient induced

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Studies of bipolar disorder, particularly neuroimaging studies, are vulnerable to the confounding effects such as medication, comorbidity, and small sample size, leading to underpowered independent studies, and significant heterogeneity.

429:, which has been reported in functional neuroimaging studies to be abnormal in bipolar mania. Specifically, reduced blood flow to the lateral OFC has been reported, and may reflect dysfunction that leads to the neurocognitive deficits. 775:

Increased combined glutamine and glutamate (Glx) have been observed globally, regardless of medication status. Increased Glx has been associated with reduced frontal mismatch negativity, interpreted as dysfunction in NMDA signaling.

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Nery, FG; Monkul, ES; Lafer, B (December 2013). "Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: A review of neuroimaging studies of individuals at high genetic risk for bipolar disorder".

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amygdala, possibly involving impaired synaptic pruning, although this may reflect medication or compensatory effects; that is, these abnormalities may not be involved in the mechanism of bipolar, and may instead be a consequence.

1777:

Jiang, HY; Qiao, F; Xu, XF; Yang, Y; Bai, Y; Jiang, LL (9 August 2013). "Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations".

998:

and PKC inhibition is a plausible mechanism of action for mood stabilizers. Overactive PKC signalling may lead to long term structural changes in the frontal cortex as well, potentially leading to progression of manic symptoms.

2818:

Mazza, M; Di Nicola, M; Della Marca, G; Janiri, L; Bria, P; Mazza, S (August 2007). "Bipolar disorder and epilepsy: a bidirectional relation? Neurobiological underpinnings, current hypotheses, and future research directions".

263:

Mania occurs secondary to neurological conditions between a rate of 2% to 30%. Mania is most commonly seen in right sided lesions, lesions that disconnect the prefrontal cortex, or excitatory lesions in the left hemisphere.

4913:

Fernandes, BS; Molendijk, ML; Köhler, CA; Soares, JC; Leite, CM; Machado-Vieira, R; Ribeiro, TL; Silva, JC; Sales, PM; Quevedo, J; Oertel-Knöchel, V; Vieta, E; González-Pinto, A; Berk, M; Carvalho, AF (30 November 2015).

244:

in around 30% of people with bipolar. While not all people with bipolar demonstrate seasonality of affective symptoms, it is a consistently reported feature that supports theories of circadian dysfunction in bipolars.

489:

prefrontal regions. Based on this, it has been suggested that reduced limbic regulation by prefrontal regions plays a role in bipolar. Findings related to the volume of the basal ganglia have been inconsistent.

463:) can be efficacious in treating mania. While a large body of translational evidence exists to support DAT hypofunction, in vivo evidence is limited to one study reporting reduced DAT binding in the caudate. 3445:

O'Brien, JT; Pezzoli, S; Phillips, ML; Sachdev, PS; Salvadore, G; Selvaraj, S; Stanfield, AC; Thomas, AJ; van Tol, MJ; van der Wee, NJA; Veltman, DJ; Young, AH; Fu, CH; Cleare, AJ; Arnone, D (October 2017).

4361:

Chitty, KM; Lagopoulos, J; Lee, RS; Hickie, IB; Hermens, DF (November 2013). "A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder".

540:

White matter is reduced in the posterior corpus callosum, regions adjacent to the anterior cingulate, the left optic radiation, and right superior longitudinal tract, and increased in the cerebellum and

442:

Neuroimaging studies are consistent with trait hypersensitivity in reward systems, as both mania and depression is associated with elevated resting activity in the striatum, and elevated activity in the

4318:

Gigante, AD; Bond, DJ; Lafer, B; Lam, RW; Young, LT; Yatham, LN (August 2012). "Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis".

4516:

Lyoo, Kyoon; Renshaw, Perry (2010). "Functional Magnetic Resonance Imaging, Diffusion Tensor Imaging, and Magnetic Resonance Spectroscopy in Bipolar Disorder". In Yatham, Lakshmi; Maj, Mario (eds.).

943:

but not other G proteins is increased in the frontal, temporal and occipital cortices. The binding of serotonin receptors to G proteins is also elevated globally. Leukocyte and platelet levels of G

3638:

Selvaraj, S; Arnone, D; Job, D; Stanfield, A; Farrow, TF; Nugent, AC; Scherk, H; Gruber, O; Chen, X; Sachdev, PS; Dickstein, DP; Malhi, GS; Ha, TH; Ha, K; Phillips, ML; McIntosh, AM (March 2012).

391:

about bipolar. This observation led to the first experiments with anticonvulsants in bipolar, which are effective in stabilizing mood. Studies reporting reduced markers of inhibitory interneurons

2862:

Brooks, John O; Wang, PoW; Ketter, Terence A (2010). "Functional Brain Imaging Studies in Bipolar Disorder: Focus on Cerebral Metabolism and Blood Flow". In Yatham, Lakshmi N; Maj, Mario (eds.).

340:

The main loci of neuroimaging and neuropathological findings in bipolar have been proposed to constitute dysfunction in a "visceromotor" network, composed of the medial prefrontal cortex (mPFC),

31:

individuals to developing bipolar disorder. Neuroimaging and postmortem studies have found abnormalities in a variety of brain regions, and most commonly implicated regions include the ventral

3316:

Usher, J; Leucht, S; Falkai, P; Scherk, H (30 April 2010). "Correlation between amygdala volume and age in bipolar disorder - a systematic review and meta-analysis of structural MRI studies".

4109:

Hajek, T; Alda, M; Hajek, E; Ivanoff, J (December 2013). "Functional neuroanatomy of response inhibition in bipolar disorders--combined voxel based and cognitive performance meta-analysis".

1008:

have been shown to increase its phosphorylation, thereby inhibiting it. However, some postmortem studies have not shown any differences in GSK-3 levels or the levels of a downstream target

537:

One meta analysis reported that when correcting for lithium treatment, which was associated with increased hippocampal volume, people with bipolar demonstrate reduced hippocampus volume.

863:

is also elevated in bipolar I patients with a history of psychosis, although this finding is inconsistent with finding that valproate increases VMAT2 expression in rodents. One study on

3562:

Kempton, MJ; Geddes, JR; Ettinger, U; Williams, SC; Grasby, PM (September 2008). "Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder".

438:

attenuate manic behavior, and co-morbid ADHD and bipolar are effectively treated with stimulants), and the mechanism of antimanic drugs may involve attenuating dopamine signalling.

3830:

Pezzoli, S; Emsell, L; Yip, SW; Dima, D; Giannakopoulos, P; Zarei, M; Tognin, S; Arnone, D; James, A; Haller, S; Frangou, S; Goodwin, GM; McDonald, C; Kempton, MJ (January 2018).

1987:"The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects" 808:

null findings, or even elevated levels of NAA in the frontal cortex. In unmedicated populations, reduced NAA consistently found in the prefrontal cortex, particularly the dlPFC.

39:. Dysfunction in emotional circuits located in these regions have been hypothesized as a mechanism for bipolar disorder. A number of lines of evidence suggests abnormalities in 2296:

Bostock, EC; Kirkby, KC; Garry, MI; Taylor, BV (1 September 2015). "Comparison of precipitating factors for mania and partial seizures: Indicative of shared pathophysiology?".

5237:

da Rosa, MI; Simon, C; Grande, AJ; Barichello, T; Oses, JP; Quevedo, J (December 2016). "Serum S100B in manic bipolar disorder patients: Systematic review and meta-analysis".

4152:

Kupferschmidt, DA; Zakzanis, KK (30 August 2011). "Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature".

5451:

Savitz, JB; Price, JL; Drevets, WC (May 2014). "Neuropathological and neuromorphometric abnormalities in bipolar disorder: view from the medial prefrontal cortical network".

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Patel, N; Nandagopal, J; Cerullo, M; Fleck, D; Adler, C; Strakowski, S; DelBello, M. "Neuroimaging Biomarkers for Bipolar Disorder Across the Lifespan". In Ritsner, M (ed.).

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Fredericks, Carolyn A; Kalmar, Jessica H; Blumberg, Hilary P (2006). "The role of the ventral prefrontal cortex in mood disorders". In Zald, David H; Rauch, Scott L (eds.).

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Strakowski, SM; Adler, CM; Almeida, J; Altshuler, LL; Blumberg, HP; Chang, KD; DelBello, MP; Frangou, S; McIntosh, A; Phillips, ML; Sussman, JE; Townsend, JD (June 2012).

3917:

Brooks III, John; Ketter, Terrence; Wang, Po (2010). "Functional Imaging Studies in Bipolar: Focus on Cerebral Metabolism and Blood Flow". In Yatham, L; Maj, M (eds.).

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Heckers, Stephan; Woodward, Neil; Öngür, Dost (2018). "Neuroimaging of Psychotic Disorders". In Sklar, Pamela; Charney, Dennis; Buxbaum, Joseph; Nestler, Eric (eds.).

3359:

Pfeifer, JC; Welge, J; Strakowski, SM; Adler, CM; DelBello, MP (November 2008). "Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder".

915:. These abnormalities are particularly prominent in mania, and are inversely associated with antipsychotic use. The incidence of psychiatric symptoms associated with 859:

is associated with high rates of depression, and one case study has reported the abolishment of parkinson's symptoms during manic episodes. The binding potential of

3964:"A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research" 2122:

Nurnberger JI, Jr; Koller, DL; Jung, J; Edenberg, HJ; Foroud, T; Guella, I; Vawter, MP; Kelsoe, JR; Psychiatric Genomics Consortium Bipolar, Group. (June 2014).

3832:"Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data" 433:

abnormality has been associated with the cholinergic-aminergic hypothesis, which postulates elevated dopaminergic signaling in mania. Reducing the function of

2791:

Wiglusz, MS; Landowski, J; Cubała, WJ; Agius, M (September 2015). "Overlapping phenomena of bipolar disorder and epilepsy--a common pharmacological pathway".

1041: 985:(a substrate of PKA), along with increased levels of Rap1 have been reported in peripherally collected cells of people with bipolar. Increased coupling of 2334:

Satzer, D; Bond, DJ (May 2016). "Mania secondary to focal brain lesions: implications for understanding the functional neuroanatomy of bipolar disorder".

123:

In light of associations between bipolar and circadian abnormalities (such as decreased need for sleep and increased sleep latency), polymorphisms in the

1061:

A number of abnormalities in GABAergic neurons have been reported in people with bipolar disorder. People with bipolar demonstrate reduced expression of

799:

in the basal ganglia, and cingulate as well as a decrease in NAA in the dlPFC and hippocampus. State-specific findings were reported to include elevated

120:. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa. 1012:. In contrast, one review reported a number of studies observing reduced expression of β-catenin and GSK3 mRNA in the prefrontal and temporal cortex. 954:

are also elevated in those with bipolar disorder. Downstream targets of G protein signaling are also altered in bipolar disorder. Increased levels of

4481:

Silverstone, PH; McGrath, BM; Kim, H (February 2005). "Bipolar disorder and myo-inositol: a review of the magnetic resonance spectroscopy findings".

3171:

Rizvi, SJ; Lambert, C; Kennedy, S (8 March 2018). "Presentation and Neurobiology of Anhedonia in Mood Disorders: Commonalities and Distinctions".

887: 3447:"Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis" 1592:"Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder" 3949:

The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes: Volume II: Neuroanatomical and Neuroimaging Endophenotypes and Biomarkers

2598:

Strakowski, SM; Delbello, MP; Adler, CM (January 2005). "The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings".

4773: 3882:

Chen, CH; Suckling, J; Lennox, BR; Ooi, C; Bullmore, ET (February 2011). "A quantitative meta-analysis of fMRI studies in bipolar disorder".

3428: 2704:

Green, MJ; Cahill, CM; Malhi, GS (November 2007). "The cognitive and neurophysiological basis of emotion dysregulation in bipolar disorder".

1936:"Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis" 2077:"Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes" 425:

set shifting, and planning. The clinical phenomenology and neurocognitive deficits are similar to those seen in patients with damage to the

5584: 1365:

Bearden, C; Zandi, P; Freimer, N. "Molecular Architecture and Neurobiology of Bipolar Disorder". In Lehner, T; Miller, B; State, M (eds.).

510:

in grey matter volume reduction occurs in the anterior cingulate cortex, medial prefrontal cortex, lateral prefrontal cortex and bilateral

369: 1720:"A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response" 855:(CSF) of people with depression is consistently reported. This finding is related to psychomotor retardation and anhedonia. Furthermore, 387:

Lateralized seizure sequelae similar to bipolar has been reported in people with mesial temporal lobe seizures, and provides support for

5594: 1089:

have also been reported, which, along with abnormal glutamate signaling, could contribute to reduced GABAergic tone in the hippocampus.

3519:

Bora, E; Fornito, A; Yücel, M; Pantelis, C (1 June 2010). "Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder".

2896: 3023:"Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies" 2744:"Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala-anterior paralimbic neural system" 1049:

concentrations have also been reported. Mitochondrial dysfunction may be related to elevated levels of the lipid peroxidation marker

886:

One more line of evidence that suggests a role of monoamines in bipolar is the process of antidepressant related affective switches.

4998: 4013:"Elevated reward-related neural activation as a unique biological marker of bipolar disorder: assessment and treatment implications" 3503: 3419:

Brambilla, Paolo; Soares, Jair (2010-10-11). "Structural Brain Imaging in Bipolar Disorder". In Lakshmi, Yatham; Maj, Mario (eds.).

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Pedroso, I; Lourdusamy, A; Rietschel, M; Nöthen, MM; Cichon, S; McGuffin, P; Al-Chalabi, A; Barnes, MR; Breen, G (15 August 2012).

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Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Långström N, Hultman CM (2008). "Advancing Paternal Age and Bipolar Disorder".

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Gawryluk, J; Young, T. "Signal Transduction Pathways in the Pathophysiology of Bipolar Disorder". In Manji, H; Zarate, C (eds.).

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González-Castro, TB; Nicolini, H; Lanzagorta, N; López-Narváez, L; Genis, A; Pool García, S; Tovilla-Zárate, CA (February 2015).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

3269:"Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group" 2423:

Savitz, J; Drevets, W (2011). "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

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Smith, Daniel; Whitham, Elizabeth; Ghaemi, Nassir (2012). "Bipolar Disorder". In Schlaepfer, Thomas; Nemeroff, Charles (eds.).

1073:. More extensive reductions of other indicators of GABA function have been reported in the CA4 and CA1. Abnormal expression of 792: 635: 482: 217:

has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new

168: 5599: 963: 781: 658: 486: 196: 5332:

Fountoulakis, KN (2012). "The possible involvement of NMDA glutamate receptor in the etiopathogenesis of bipolar disorder".

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DelBello, MP; Adler, CM; Strakowski, SM (April 2006). "The neurophysiology of childhood and adolescent bipolar disorder".

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in acutely depressed bipolar. Serotonin may play a role in mania by increasing the salience of stimuli related to reward.

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Schür, RR; Draisma, LW; Wijnen, JP; Boks, MP; Koevoets, MG; Joëls, M; Klomp, DW; Kahn, RS; Vinkers, CH (September 2016).

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Savitz, J; Drevets, W. "Neuroimaging and Neuropathological Findings in Bipolar Disorder". In H, Manji; Zarate, C (eds.).

3124:"The development and course of bipolar spectrum disorders: an integrated reward and circadian rhythm dysregulation model" 4989:; Feng Wang, Jun; Young, Trevor (2010). "Molecular Biology of Bipolar Disorder". In Yatham, Lakshmi; Maj, Mario (eds.). 4898:

Dinan, Timothy; Bauer, Michael (2010). "Neuroendocrinology of Bipolar Disorder". In Yatham, Lakshmi; Maj, Mario (eds.).

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Hegerl, Ulrich; Sander, Christian; Hensch, Tilman. "Arousal Regulation in Affective Disorders". In Frodl, Thomas (ed.).

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Strakowski, Stephen M. (2011). "Structural Imaging of Bipolar Illness". In Shenton, Martha E; Turetsky, Bruce I (eds.).

4916:"Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies" 4533:"Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies" 5543:

Elhaik, E; Zandi, P (November 2015). "Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder".

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Young, Trevor; Cintoh, Arabah. "Understanding the Neurobiology of Bipolar Depression". In Zarate, C; Manji, H (eds.).

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Gigante, AD; Young, LT; Yatham, LN; Andreazza, AC; Nery, FG; Grinberg, LT; Heinsen, H; Lafer, B (September 2011).

3783:"Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis" 1482:"Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4" 5604: 891: 847:

The role of monoamines in bipolar have been studied using neurotransmitter metabolites. Reduced concentration of

341: 5369:"Morphometric post-mortem studies in bipolar disorder: possible association with oxidative stress and apoptosis" 2512:

Cerullo, MA; Adler, CM; Delbello, MP; Strakowski, SM (2009). "The functional neuroanatomy of bipolar disorder".

5289:

Bipolar Depression: Molecular Neurobiology, Clinical Diagnosis and Pharmacotherapy (Milestones in Drug Therapy)

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include hyperactivation in the basal ganglia. A meta analysis of fMRI studies reported underactivations in the

565:

During cognitive or emotional tasks, functional neuroimaging studies, consistently find hyperactivation of the

1350:

Sklar, P. "The Genetics of Schizophrenia and Bipolar Disorder". In Charney, D; Buxmaum, J; Nestler, E (eds.).

5589: 966:

induced PKA activity are also reported. Phosphoinositide signaling is also altered, with elevated levels of

598: 300: 1146:

Townsend, J; Altshuler, LL (June 2012). "Emotion processing and regulation in bipolar disorder: a review".

5041:

Saxena, A; Scaini, G; Bavaresco, DV; Leite, C; Valvassoria, SS; Carvalho, AF; Quevedo, J (November 2017).

4597:

van Enkhuizen, J; Janowsky, DS; Olivier, B; Minassian, A; Perry, W; Young, JW; Geyer, MA (15 April 2015).

856: 582: 324: 320: 153: 1383:"Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder" 1037: 876: 777: 184: 137: 2633:

Adler, CM; DelBello, MP; Strakowski, SM (April 2006). "Brain network dysfunction in bipolar disorder".

928:

Brain derived neurotrophic factor levels are peripherally reduced in both manic and depressive phases.

163:

Val66Met allele and bipolar disorder, except possibly in a subgroup of bipolar II cases, and suicide.

3932:

Blond, B; Blumberg, H. "Functional Neuroimaging Research in Bipolar". In Manji, H; Zarate, C (eds.).

1731: 1543: 1189:

Newberg, AR; Catapano, LA; Zarate, CA; Manji, HK (January 2008). "Neurobiology of bipolar disorder".

867:

binding in acutely depressed people with bipolar reported reductions in the caudate but not putamen.

864: 836: 832: 828: 460: 448: 434: 426: 345: 268: 248:

Risk factors for bipolar include obstetric complications, abuse, drug use, and major life stressors.

4060:

Wegbreit, E; Cushman, GK; Puzia, ME; Weissman, AB; Kim, KL; Laird, AR; Dickstein, DP (August 2014).

3072:"Iowa Gambling Task performance in euthymic bipolar I disorder: a meta-analysis and empirical study" 195:

signaling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the

43:, intracellular signalling, and cellular functioning as possibly playing a role in bipolar disorder. 4792:

Salvadore, G; Quiroz, JA; Machado-Vieira, R; Henter, ID; Manji, HK; Zarate CA, Jr (November 2010).

1066: 852: 284: 214: 224:

A meta-analysis was performed to determine the association between bipolar disorder and oxidative

5476: 5433: 4877: 4387: 4343: 4221: 4177: 4134: 3713: 3669: 3640:"Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies" 3544: 3341: 3196: 2844: 2658: 2580: 2537: 2405: 2359: 2104: 1852: 1803: 1700: 1656: 1214: 1171: 1117: 986: 780:

levels in the basal ganglia are reduced in bipolar disorder, and trends towards increased in the

296: 288: 116:

and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and

4407:"Neurometabolites in schizophrenia and bipolar disorder - a systematic review and meta-analysis" 5408:

Vawter, MP; Freed, WJ; Kleinman, JE (15 September 2000). "Neuropathology of bipolar disorder".

5560: 5525: 5468: 5425: 5390: 5349: 5254: 5219: 5170: 5121: 5072: 4994: 4947: 4869: 4823: 4769: 4716: 4672: 4649:

Manji, HK; Quiroz, JA; Payne, JL; Singh, J; Lopes, BP; Viegas, JS; Zarate, CA (October 2003).

4628: 4564: 4498: 4463: 4436: 4379: 4335: 4270: 4213: 4169: 4126: 4091: 4042: 3993: 3899: 3861: 3812: 3763: 3705: 3661: 3620: 3579: 3536: 3499: 3476: 3424: 3399: 3376: 3333: 3298: 3245: 3188: 3153: 3101: 3052: 2984: 2935: 2892: 2867: 2836: 2800: 2773: 2721: 2684: 2650: 2615: 2572: 2529: 2494: 2443: 2397: 2351: 2313: 2276: 2253: 2188: 2153: 2096: 2057: 2008: 1967: 1916: 1844: 1795: 1759: 1692: 1648: 1613: 1571: 1511: 1462: 1412: 1314: 1265: 1206: 1163: 1074: 848: 800: 542: 241: 218: 40: 32: 27: 5552: 5515: 5507: 5460: 5417: 5380: 5341: 5246: 5209: 5201: 5160: 5152: 5111: 5103: 5092:"Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications" 5062: 5054: 5023: 4937: 4927: 4859: 4851: 4813: 4805: 4706: 4662: 4618: 4610: 4554: 4544: 4490: 4426: 4418: 4371: 4327: 4260: 4252: 4205: 4161: 4118: 4081: 4073: 4032: 4024: 3983: 3975: 3891: 3851: 3843: 3802: 3794: 3753: 3745: 3697: 3651: 3610: 3571: 3528: 3466: 3458: 3368: 3325: 3288: 3280: 3235: 3227: 3180: 3143: 3135: 3091: 3083: 3042: 3034: 2974: 2966: 2925: 2828: 2763: 2755: 2713: 2642: 2607: 2564: 2521: 2484: 2476: 2389: 2343: 2305: 2243: 2235: 2180: 2143: 2135: 2088: 2047: 2039: 1998: 1957: 1947: 1906: 1898: 1834: 1787: 1749: 1739: 1684: 1640: 1603: 1561: 1551: 1501: 1493: 1452: 1444: 1402: 1394: 1304: 1296: 1255: 1245: 1198: 1155: 1101: 1016: 994: 975: 971: 959: 955: 948: 937: 713: 527: 19: 4405:

Kraguljac, NV; Reid, M; White, D; Jones, R; den Hollander, J; Lowman, D; Lahti, AC (2012).

3597:

Arnone, D; Cavanagh, J; Gerber, D; Lawrie, SM; Ebmeier, KP; McIntosh, AM (September 2009).

3021:

van Enkhuizen, J; Geyer, MA; Minassian, A; Perry, W; Henry, BL; Young, JW (November 2015).

3139: 1872:

Neurobiology of Brain Disorder: Biological Basis of Neurological and Psychiatric Disorders

967: 676: 590: 519: 188: 176: 3599:"Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis" 3267:

Goikolea, J M; Houenou, J; Beard, L M; Rauer, L; Abramovic, L; et al. (2 May 2017).

1104:

is found in the medial prefrontal cortex, and is possibly specific to GABAergic neurons.

1093:

for reduced NMDA signaling and reduced contribution from the NR2A subunit is consistent.

552:

Bilaterally reduced activity in the inferior frontal gyrus (BA47). Image at Talairach z=2

172: 2224:"Investigating the mechanism(s) underlying switching between states in bipolar disorder" 1735: 1547: 758:

mRNA, neuronal volume in layer I, and microstructural integrity in people with bipolar.

751:), which is congruent with the abnormal structural connectivity observed in the region. 455:

can precipitate mania, and drugs that attenuate dopaminergic signaling extracellularly (

5520: 5495: 5214: 5189: 5165: 5140: 5116: 5091: 5067: 5042: 4942: 4915: 4818: 4793: 4667: 4650: 4623: 4598: 4559: 4532: 4431: 4406: 4265: 4240: 4086: 4061: 4037: 4012: 3988: 3963: 3856: 3831: 3807: 3782: 3758: 3733: 3471: 3446: 3293: 3268: 3240: 3216:"Reward processing dysfunction in major depression, bipolar disorder and schizophrenia" 3215: 3148: 3123: 3096: 3071: 3047: 3022: 2979: 2954: 2768: 2743: 2489: 2464: 2393: 2248: 2148: 2123: 2052: 2027: 1962: 1935: 1911: 1886: 1754: 1719: 1506: 1481: 1457: 1432: 1407: 1382: 1309: 1284: 1260: 1233: 916: 670: 531: 511: 308: 292: 252: 5421: 5156: 4422: 4165: 3329: 1644: 597:

activity was reported in the parahippocampal, superior temporal, middle temporal, and

5578: 5556: 4986: 4494: 4331: 4122: 4062:"Developmental meta-analyses of the functional neural correlates of bipolar disorder" 3895: 3656: 3639: 2970: 2759: 2480: 2409: 1300: 1159: 1113: 904: 744: 566: 507: 456: 5464: 4881: 4599:"The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited" 4391: 4375: 4209: 4138: 4077: 3847: 3548: 3345: 3038: 2662: 2584: 2541: 2363: 2139: 2108: 1807: 1704: 1218: 1175: 140:, although the study was specific to European populations. Two polymorphisms in the 5480: 5437: 4855: 4347: 4225: 4181: 3979: 3673: 3532: 3200: 2848: 2092: 1856: 1660: 1009: 895:

perturbation in monoamine systems is associated with more frequent mood switching.

880: 353: 312: 192: 77: 46: 5043:"Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature" 3717: 1480:

Psychiatric GWAS Consortium Bipolar Disorder Working, Group. (18 September 2011).

1433:"Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder" 136:. One meta analysis reported a significant association of the short allele of the 4614: 3372: 3231: 2832: 2239: 1791: 1744: 1688: 1566: 879:

binding in the insula, mPFC, ACC and thalamus, and decreased SERT binding in the

526:

The ENIGMA bipolar disorder working group reported cortical thinning in the left

2043: 1086: 1070: 1046: 811:

One meta-analysis reported no changes in MRS measured GABA in bipolar disorder.

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The orbitofrontal cortex demonstrates reduced grey matter, functional activity,

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mRNA in the CA2/CA3 being found in people with bipolar. Decreased levels of

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has been implicated in bipolar disorder, as bipolar medications lithium and

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being reported in bipolar. Elevated cAMP stimulated phosphorylation or

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meta-analysis of functional magnetic resonance imaging studies".

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abnormal serotonin signaling. One study reported both increased

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