Editing Mania (section)

== Mechanism ==
{{Further|Biology of bipolar disorder}}
The mechanism underlying mania is unknown, but the neurocognitive profile of mania is highly consistent with dysfunction in the right [[prefrontal cortex]], a common finding in neuroimaging studies.<ref>{{cite journal|last1=Clark|first1=L|last2=Sahakian|first2=BJ|title=Cognitive neuroscience and brain imaging in bipolar disorder.|journal=Dialogues in Clinical Neuroscience|date=2008|volume=10|issue=2|pages=153–63|doi=10.31887/DCNS.2008.10.2/lclark|pmid=18689286|pmc=3181872}}</ref><ref name="Arnsten">{{cite journal|last1=Arnsten|first1=AFT|last2=Manji|first2=HK|last3=Haberland|first3=G|title=Mania: a rational neurobiology|journal=Future Neurology|date=March 2008|volume=3|issue=2|pages=125–131|doi=10.2217/14796708.3.2.125}}</ref> Various lines of evidence from post-mortem studies and the putative mechanisms of anti-manic agents point to abnormalities in [[Glycogen synthase kinase 3|GSK-3]],<ref name="pmid21040291">{{cite journal |vauthors=Li X, Liu M, Cai Z, Wang G, Li X | title = Regulation of glycogen synthase kinase-3 during bipolar mania treatment | journal = Bipolar Disord | volume = 12 | issue = 7 | pages = 741–52 | year = 2010 | pmid = 21040291 | pmc = 3059222 | doi = 10.1111/j.1399-5618.2010.00866.x }}</ref> [[dopamine]], [[Protein kinase C]], and [[Inositol monophosphatase]].<ref name="GG">{{cite book  | last1 = Goodman | first1 = Brunton L, Chabner B, Knollman B | title = Goodman Gilman's pharmacological basis of therapeutics | date = 2011 | publisher = McGraw-Hill Professional  | location = New York | isbn = 978-0-07-162442-8 | edition = Twelfth }}</ref>

Meta analysis of neuroimaging studies demonstrate increased [[Thalamus|thalamic]] activity, and bilaterally reduced inferior [[Frontal gyri|frontal gyrus]] activation.<ref>{{cite journal|last1=Chen|first1=CH|last2=Suckling|first2=J|last3=Lennox|first3=BR|last4=Ooi|first4=C|last5=Bullmore|first5=ET|title=A quantitative meta-analysis of fMRI studies in bipolar disorder.|journal=Bipolar Disorders|date=February 2011|volume=13|issue=1|pages=1–15|doi=10.1111/j.1399-5618.2011.00893.x|pmid=21320248}}</ref> Activity in the [[amygdala]] and other subcortical structures such as the [[ventral striatum]] tend to be increased, although results are inconsistent and likely dependent upon task characteristics such as valence. Reduced functional connectivity between the ventral prefrontal cortex and amygdala along with variable findings supports a hypothesis of general dysregulation of subcortical structures by the prefrontal cortex.<ref>{{cite journal|last1=Strakowski|first1=SM|last2=Adler|first2=CM|last3=Almeida|first3=J|last4=Altshuler|first4=LL|last5=Blumberg|first5=HP|last6=Chang|first6=KD|last7=DelBello|first7=MP|last8=Frangou|first8=S|last9=McIntosh|first9=A|last10=Phillips|first10=ML|last11=Sussman|first11=JE|last12=Townsend|first12=JD|title=The functional neuroanatomy of bipolar disorder: a consensus model.|journal=Bipolar Disorders|date=June 2012|volume=14|issue=4|pages=313–25|doi=10.1111/j.1399-5618.2012.01022.x|pmid=22631617|pmc=3874804}}</ref> A bias towards [[Valence (psychology)|positively valenced stimuli]], and increased responsiveness in [[reward circuitry]] may predispose towards mania.<ref>{{cite journal|last1=Phillips|first1=ML|last2=Swartz|first2=HA|title=A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research.|journal=The American Journal of Psychiatry|date=August 2014|volume=171|issue=8|pages=829–43|doi=10.1176/appi.ajp.2014.13081008|pmid=24626773|pmc=4119497}}</ref> Mania tends to be associated with right hemisphere lesions, while depression tends to be associated with left hemisphere lesions.<ref>{{cite journal|last1=Braun|first1=CM|last2=Larocque|first2=C|last3=Daigneault|first3=S|last4=Montour-Proulx|first4=I|title=Mania, pseudomania, depression, and pseudodepression resulting from focal unilateral cortical lesions.|journal=Neuropsychiatry, Neuropsychology & Behavioral Neurology|date=January 1999|volume=12|issue=1|pages=35–51|pmid=10082332}}</ref>

Post-mortem examinations of bipolar disorder demonstrate increased expression of [[Protein kinase C|Protein Kinase C]] (PKC).<ref name="Signal Transduction">{{cite book|last1=Gawryluk|first1=J|last2=Young|first2=T|editor1-last=Manji|editor1-first=H|editor2-last=Zarate|editor2-first=C|title=Behavioral Neurobiology of Bipolar Disorder And its Treatment|publisher=Springer|pages=151–152|chapter=Signal Transduction Pathways in the Pathophysiology of Bipolar Disorder}}</ref> While limited, some studies demonstrate manipulation of PKC in animals produces behavioral changes mirroring mania, and treatment with PKC inhibitor [[tamoxifen]] (also an [[Antiestrogen|anti-estrogen]] drug) demonstrates antimanic effects. Traditional antimanic drugs also demonstrate PKC inhibiting properties, among other effects such as GSK3 inhibition.<ref name="Arnsten"/>

Manic episodes may be triggered by [[dopamine receptor agonists]], and this combined with tentative reports of increased [[VMAT2]] activity, measured via [[Positron emission tomography|PET scans]] of [[Radioligand binding assay|radioligand binding]], suggests
a role of dopamine in mania. Decreased cerebrospinal fluid levels of the serotonin metabolite [[5-HIAA]] have been found in manic patients too, which may be explained by a failure of [[Serotonin|serotonergic]] regulation and [[dopaminergic]] hyperactivity.<ref>{{cite journal|last1=MANJI|first1=HUSSEINI K|last2=QUIROZ|first2=JORGE A|last3=PAYNE|first3=JENNIFER L|last4=SINGH|first4=JASKARAN|last5=LOPES|first5=BARBARA P|last6=VIEGAS|first6=JENILEE S|last7=ZARATE|first7=CARLOS A|title=The underlying neurobiology of bipolar disorder|journal=World Psychiatry|date=Oct 2003|volume=2|issue=3|pages=136–146|issn=1723-8617|pmc=1525098|pmid=16946919}}</ref>

Limited evidence suggests that mania is associated with behavioral reward hypersensitivity, as well as with neural reward hypersensitivity. Electrophysiological evidence supporting this comes from studies associating left frontal [[Electroencephalography|EEG]] activity with mania. As left frontal EEG activity is generally thought to be a reflection of [[Gray's biopsychological theory of personality|behavioral activation system]] activity, this is thought to support a role for reward hypersensitivity in mania. Tentative evidence also comes from one study that reported an association between manic traits and feedback negativity during receipt of monetary reward or loss. Neuroimaging evidence during acute mania is sparse, but one study reported elevated [[orbitofrontal cortex]] activity to monetary reward, and another study reported elevated striatal activity to reward omission. The latter finding was interpreted in the context of either elevated baseline activity (resulting in a null finding of reward hypersensitivity), or reduced ability to discriminate between reward and punishment, still supporting reward hyperactivity in mania.<ref>{{cite journal|last1=Nusslock|first1=Robin|last2=Young|first2=Christina B.|last3=Damme|first3=Katherine S. F.|title=Elevated reward-related neural activation as a unique biological marker of bipolar disorder: assessment and treatment implications|journal=Behaviour Research and Therapy|date=1 November 2014|volume=62|pages=74–87|doi=10.1016/j.brat.2014.08.011|issn=1873-622X|pmid=25241675|pmc=6727647}}</ref> Punishment [[hyposensitivity]], as reflected in a number of neuroimaging studies as reduced lateral orbitofrontal response to punishment, has been proposed as a mechanism of reward hypersensitivity in mania.<ref>{{cite journal|last1=Rolls|first1=ET|title=A non-reward attractor theory of depression.|journal=Neuroscience and Biobehavioral Reviews|date=September 2016|volume=68|pages=47–58|doi=10.1016/j.neubiorev.2016.05.007|pmid=27181908|s2cid=8145667|url=http://wrap.warwick.ac.uk/80548/1/WRAP_Rolls_depression16c.pdf|access-date=2018-12-19|archive-date=2018-07-19|archive-url=https://web.archive.org/web/20180719010519/http://wrap.warwick.ac.uk/80548/1/WRAP_Rolls_depression16c.pdf|url-status=live}}</ref>