Editing Working memory (section)

== In the brain ==
=== Neural mechanisms of maintaining information ===
The first insights into the neuronal and neurotransmitter basis of working memory came from animal research. The work of Jacobsen<ref>{{Cite journal| vauthors = Jacobsen CF |title= Studies of cerebral function in primates |journal=Comparative Psychology Monographs |volume=13 |issue=3 |pages=1–68 |year=1938 |oclc=250695441 }}</ref> and Fulton in the 1930s first showed that lesions to the PFC impaired spatial working memory performance in monkeys. The later work of [[Joaquin Fuster]]<ref>{{cite journal | vauthors = Fuster JM | title = Unit activity in prefrontal cortex during delayed-response performance: neuronal correlates of transient memory | journal = Journal of Neurophysiology | volume = 36 | issue = 1 | pages = 61–78 | date = January 1973 | pmid = 4196203 | doi = 10.1152/jn.1973.36.1.61 | s2cid = 17534879 | doi-access = free }}</ref> recorded the electrical activity of neurons in the PFC of monkeys while they were doing a delayed matching task. In that task, the monkey sees how the experimenter places a bit of food under one of two identical-looking cups. A shutter is then lowered for a variable delay period, screening off the cups from the monkey's view. After the delay, the shutter opens and the monkey is allowed to retrieve the food from under the cups. Successful retrieval in the first attempt – something the animal can achieve after some training on the task – requires holding the location of the food in memory over the delay period. Fuster found neurons in the PFC that fired mostly during the delay period, suggesting that they were involved in representing the food location while it was invisible. Later research has shown similar delay-active neurons also in the posterior [[parietal cortex]], the [[thalamus]], the [[Caudate nucleus|caudate]], and the [[globus pallidus]].<ref>{{cite journal | vauthors = Ashby FG, Ell SW, Valentin VV, Casale MB | title = FROST: a distributed neurocomputational model of working memory maintenance | journal = Journal of Cognitive Neuroscience | volume = 17 | issue = 11 | pages = 1728–1743 | date = November 2005 | pmid = 16269109 | doi = 10.1162/089892905774589271 | s2cid = 12765957 }}</ref> The work of [[Patricia Goldman-Rakic|Goldman-Rakic]] and others showed that principal sulcal, dorsolateral PFC interconnects with all of these brain regions, and that neuronal microcircuits within PFC are able to maintain information in working memory through recurrent excitatory glutamate networks of pyramidal cells that continue to fire throughout the delay period.<ref>{{cite journal | vauthors = Goldman-Rakic PS | title = Cellular basis of working memory | journal = Neuron | volume = 14 | issue = 3 | pages = 477–485 | date = March 1995 | pmid = 7695894 | doi = 10.1016/0896-6273(95)90304-6 | s2cid = 2972281 | doi-access = free }}</ref> These circuits are tuned by lateral inhibition from GABAergic interneurons.<ref>{{cite journal | vauthors = Rao SG, Williams GV, Goldman-Rakic PS | title = Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory | journal = The Journal of Neuroscience | volume = 20 | issue = 1 | pages = 485–494 | date = January 2000 | pmid = 10627624 | pmc = 6774140 | doi = 10.1523/JNEUROSCI.20-01-00485.2000 }}</ref> The neuromodulatory arousal systems markedly alter PFC working memory function; for example, either too little or too much dopamine or norepinephrine impairs PFC network firing<ref>{{cite journal | vauthors = Arnsten AF, Paspalas CD, Gamo NJ, Yang Y, Wang M | title = Dynamic Network Connectivity: A new form of neuroplasticity | journal = Trends in Cognitive Sciences | volume = 14 | issue = 8 | pages = 365–375 | date = August 2010 | pmid = 20554470 | pmc = 2914830 | doi = 10.1016/j.tics.2010.05.003 }}</ref> and working memory performance.<ref>{{cite journal | vauthors = Robbins TW, Arnsten AF | title = The neuropsychopharmacology of fronto-executive function: monoaminergic modulation | journal = Annual Review of Neuroscience | volume = 32 | pages = 267–287 | year = 2009 | pmid = 19555290 | pmc = 2863127 | doi = 10.1146/annurev.neuro.051508.135535 }}</ref> A brain network analysis demonstrates that the FPC network requires less induced energy during working memory tasks than other functional brain networks. This finding underscores the efficient processing of the FPC network and highlights its crucial role in supporting working memory processes.<ref name="10.1038/s41598-024-83696-7">{{cite journal | vauthors = Saberi M, Rieck JR, Golafshan S, Grady CL, Misic B, Dunkley BT, Khatibi A | title = The brain selectively allocates energy to functional brain networks under cognitive control | journal = Scientific Reports | date = 2024 | volume = 14 | issue = 1 | pages = 32032 | doi = 10.1038/s41598-024-83696-7 | pmid = 39738735 | url = https://doi.org/10.1038/s41598-024-83696-7 | pmc = 11686059 | bibcode = 2024NatSR..1432032S }}</ref>

The research described above on persistent firing of certain neurons in the delay period of working memory tasks shows that the brain has a mechanism of keeping representations active without external input. Keeping representations active, however, is not enough if the task demands maintaining more than one chunk of information. In addition, the components and features of each chunk must be bound together to prevent them from being mixed up. For example, if a red triangle and a green square must be remembered at the same time, one must make sure that "red" is bound to "triangle" and "green" is bound to "square". One way of establishing such bindings is by having the neurons that represent features of the same chunk fire in synchrony, and those that represent features belonging to different chunks fire out of sync.<ref>{{cite journal | vauthors = Raffone A, Wolters G | title = A cortical mechanism for binding in visual working memory | journal = Journal of Cognitive Neuroscience | volume = 13 | issue = 6 | pages = 766–785 | date = August 2001 | pmid = 11564321 | doi = 10.1162/08989290152541430 | s2cid = 23241633 }}</ref> In the example, neurons representing redness would fire in synchrony with neurons representing the triangular shape, but out of sync with those representing the square shape. So far, there is no direct evidence that working memory uses this binding mechanism, and other mechanisms have been proposed as well.<ref>{{cite book |doi=10.1093/acprof:oso/9780198508571.003.0009 |chapter=Three forms of binding and their neural substrates: Alternatives to temporal synchrony |title=The Unity of ConsciousnessBinding, Integration, and Dissociation |date=2003 |last1=Oʼreilly |first1=Randall C. |last2=Busby |first2=Richard S. |last3=Soto |first3=Rodolfo |pages=168–190 |isbn=978-0-19-850857-1 }}</ref> It has been speculated that synchronous firing of neurons involved in working memory oscillate with frequencies in the [[theta rhythm|theta]] band (4 to 8&nbsp;Hz). Indeed, the power of theta frequency in the EEG increases with working memory load,<ref>{{Cite book|title=Handbook of binding and memory|publisher=Oxford University Press|year=2006|location=Oxford|pages=115–144|chapter=Binding principles in the theta frequency range| vauthors = Klimesch W | veditors = Zimmer HD, Mecklinger A, Lindenberger U }}</ref> and oscillations in the theta band measured over different parts of the skull become more coordinated when the person tries to remember the binding between two components of information.<ref>{{cite journal | vauthors = Wu X, Chen X, Li Z, Han S, Zhang D | title = Binding of verbal and spatial information in human working memory involves large-scale neural synchronization at theta frequency | journal = NeuroImage | volume = 35 | issue = 4 | pages = 1654–1662 | date = May 2007 | pmid = 17379539 | doi = 10.1016/j.neuroimage.2007.02.011 | s2cid = 7676564 }}</ref>

=== Localization in the brain ===
Localization of brain functions in humans has become much easier with the advent of [[brain imaging]] methods ([[Positron emission tomography|PET]] and [[fMRI]]). This research has confirmed that areas in the PFC are involved in working memory functions. During the 1990s much debate had centered on the different functions of the ventrolateral (i.e.,&nbsp;lower areas) and the [[Dorsolateral prefrontal cortex|dorsolateral (higher) areas of the PFC]]. A human lesion study provides additional evidence for the role of the [[dorsolateral prefrontal cortex]] in working memory.<ref>{{cite journal | vauthors = Barbey AK, Koenigs M, Grafman J | title = Dorsolateral prefrontal contributions to human working memory | journal = Cortex; A Journal Devoted to the Study of the Nervous System and Behavior | volume = 49 | issue = 5 | pages = 1195–1205 | date = May 2013 | pmid = 22789779 | pmc = 3495093 | doi = 10.1016/j.cortex.2012.05.022 }}</ref> One view was that the dorsolateral areas are responsible for spatial working memory and the ventrolateral areas for non-spatial working memory. Another view proposed a functional distinction, arguing that ventrolateral areas are mostly involved in pure maintenance of information, whereas dorsolateral areas are more involved in tasks requiring some processing of the memorized material. The debate is not entirely resolved but most of the evidence supports the functional distinction.<ref>{{cite journal | vauthors = Owen AM | title = The functional organization of working memory processes within human lateral frontal cortex: the contribution of functional neuroimaging | journal = The European Journal of Neuroscience | volume = 9 | issue = 7 | pages = 1329–1339 | date = July 1997 | pmid = 9240390 | doi = 10.1111/j.1460-9568.1997.tb01487.x | s2cid = 2119538 }}</ref>

Brain imaging has revealed that working memory functions are not limited to the PFC. A review of numerous studies<ref>{{cite journal | vauthors = Smith EE, Jonides J | title = Storage and executive processes in the frontal lobes | journal = Science | volume = 283 | issue = 5408 | pages = 1657–1661 | date = March 1999 | pmid = 10073923 | doi = 10.1126/science.283.5408.1657 | bibcode = 1999Sci...283.1657. }}</ref> shows areas of activation during working memory tasks scattered over a large part of the cortex. There is a tendency for spatial tasks to recruit more right-hemisphere areas, and for verbal and object working memory to recruit more left-hemisphere areas. The activation during verbal working memory tasks can be broken down into one component reflecting maintenance, in the left posterior parietal cortex, and a component reflecting subvocal rehearsal, in the left frontal cortex (Broca's area, known to be involved in speech production).<ref>{{cite journal | vauthors = Smith EE, Jonides J, Marshuetz C, Koeppe RA | title = Components of verbal working memory: evidence from neuroimaging | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 3 | pages = 876–882 | date = February 1998 | pmid = 9448254 | pmc = 33811 | doi = 10.1073/pnas.95.3.876 | doi-access = free | bibcode = 1998PNAS...95..876S }}</ref>

There is an emerging consensus that most working memory tasks recruit a network of PFC and parietal areas. A study has shown that during a working memory task the connectivity between these areas increases.<ref>{{cite journal | vauthors = Honey GD, Fu CH, Kim J, Brammer MJ, Croudace TJ, Suckling J, Pich EM, Williams SC, Bullmore ET | display-authors = 6 | title = Effects of verbal working memory load on corticocortical connectivity modeled by path analysis of functional magnetic resonance imaging data | journal = NeuroImage | volume = 17 | issue = 2 | pages = 573–582 | date = October 2002 | pmid = 12377135 | doi = 10.1016/S1053-8119(02)91193-6 }}</ref> Another study has demonstrated that these areas are necessary for working memory, and not simply activated accidentally during working memory tasks, by temporarily blocking them through [[transcranial magnetic stimulation]] (TMS), thereby producing an impairment in task performance.<ref>{{cite journal | vauthors = Mottaghy FM | title = Interfering with working memory in humans | journal = Neuroscience | volume = 139 | issue = 1 | pages = 85–90 | date = April 2006 | pmid = 16337091 | doi = 10.1016/j.neuroscience.2005.05.037 | s2cid = 20079590 }}</ref>

A current debate concerns the function of these brain areas. The PFC has been found to be active in a variety of tasks that require executive functions.<ref name="Kane MJ, Engle RW 2002 637–71" /> This has led some researchers to argue that the role of PFC in working memory is in controlling attention, selecting strategies, and manipulating information in working memory, but not in maintenance of information. The maintenance function is attributed to more posterior areas of the brain, including the parietal cortex.<ref>{{cite journal | vauthors = Curtis CE, D'Esposito M | title = Persistent activity in the prefrontal cortex during working memory | journal = Trends in Cognitive Sciences | volume = 7 | issue = 9 | pages = 415–423 | date = September 2003 | pmid = 12963473 | doi = 10.1016/S1364-6613(03)00197-9 | s2cid = 15763406 }}</ref><ref name="Postle">{{cite journal | vauthors = Postle BR | title = Working memory as an emergent property of the mind and brain | journal = Neuroscience | volume = 139 | issue = 1 | pages = 23–38 | date = April 2006 | pmid = 16324795 | pmc = 1428794 | doi = 10.1016/j.neuroscience.2005.06.005 }}</ref> Other authors interpret the activity in parietal cortex as reflecting [[executive functions]], because the same area is also activated in other tasks requiring attention but not memory.<ref>{{cite journal | vauthors = Collette F, Hogge M, Salmon E, Van der Linden M | title = Exploration of the neural substrates of executive functioning by functional neuroimaging | journal = Neuroscience | volume = 139 | issue = 1 | pages = 209–221 | date = April 2006 | pmid = 16324796 | doi = 10.1016/j.neuroscience.2005.05.035 | hdl-access = free | s2cid = 15473485 | hdl = 2268/5937 }}</ref> Evidence from decoding studying employing multi-voxel-pattern-analysis of fMRI data showed the content of visual working memory can be decoded from activity patterns in visual cortex, but not prefrontal cortex.<ref name=":5">{{cite journal | vauthors = Sreenivasan KK, Curtis CE, D'Esposito M | title = Revisiting the role of persistent neural activity during working memory | journal = Trends in Cognitive Sciences | volume = 18 | issue = 2 | pages = 82–89 | date = February 2014 | pmid = 24439529 | pmc = 3964018 | doi = 10.1016/j.tics.2013.12.001 }}</ref> This led to the suggestion that the maintenance function of visual working memory is performed by visual cortex while the role of the prefrontal cortex is in executive control over working memory<ref name=":5" /> though it has been pointed out that such comparisons do not take into account the base rate of decoding across different regions.<ref>{{cite journal | vauthors = Bhandari A, Gagne C, Badre D | title = Just above Chance: Is It Harder to Decode Information from Prefrontal Cortex Hemodynamic Activity Patterns? | journal = Journal of Cognitive Neuroscience | volume = 30 | issue = 10 | pages = 1473–1498 | date = October 2018 | pmid = 29877764 | doi = 10.1162/jocn_a_01291 | s2cid = 46954312 }}</ref>

A 2003 meta-analysis of 60 neuroimaging studies found left [[Frontal lobe|frontal]] cortex was involved in low-task demand verbal working memory and right [[Frontal lobe|frontal]] cortex for spatial working memory. Brodmann's areas (BAs) [[Brodmann area 6|6]], [[Brodmann area 8|8]], and [[Brodmann area 9|9]], in the [[Superior frontal gyrus|superior frontal cortex]] was involved when working memory must be continuously updated and when memory for temporal order had to be maintained. Right Brodmann [[Brodmann area 10|10]] and [[Brodmann area 47|47]] in the ventral frontal cortex were involved more frequently with demand for manipulation such as dual-task requirements or mental operations, and Brodmann 7 in the [[posterior parietal cortex]] was also involved in all types of executive function.<ref>{{cite journal | vauthors = Wager TD, Smith EE | title = Neuroimaging studies of working memory: a meta-analysis | journal = Cognitive, Affective & Behavioral Neuroscience | volume = 3 | issue = 4 | pages = 255–274 | date = December 2003 | pmid = 15040547 | doi = 10.3758/cabn.3.4.255 | doi-access = free }}</ref> Updating information in visual working memory is also influenced by the functional neural network connecting different brain regions.<ref name=":6">{{Cite journal |last=Velichkovsky |first=B. B. |last2=Kozlovskiy |first2=S. A. |last3=Buldakova |first3=N. S. |last4=Ushakov |first4=V. L. |last5=Kartashov |first5=S. I. |last6=Vartanov |first6=A. V. |date=2018-10-01 |title=The neurocognitive mechanisms of working memory updating |url=https://linkinghub.elsevier.com/retrieve/pii/S0167876018307931 |journal=International Journal of Psychophysiology |series= |volume=131 |pages=S171–S172 |doi=10.1016/j.ijpsycho.2018.07.452 |issn=0167-8760|url-access=subscription }}</ref> The [[Dorsolateral prefrontal cortex|dorsolateral PFC]] plays a crucial role in this process. In particular, the [[middle frontal gyrus]] may be involved in the maintenance, and the frontal operculum in the controlled processing of materials in working memory.<ref name=":6" /> Studies have also shown the role of attentional switching in working memory updating, mediated by the [[superior parietal lobule]].<ref name=":6" /> Working memory updating also involves a repetition mechanism mediated by the temporal cortex.<ref name=":6" /> And in addition, the process of working memory updating involves the sensory cortex to encode and store certain visual stimuli, such as geometric shapes ([[inferior occipital gyrus]]) and faces ([[fusiform gyrus]]).<ref name=":6" />

Working memory has been suggested to involve two processes with different neuroanatomical locations in the frontal and parietal lobes.<ref name="Bledowski">{{cite journal | vauthors = Bledowski C, Rahm B, Rowe JB | title = What 'works' in working memory? Separate systems for selection and updating of critical information | journal = The Journal of Neuroscience | volume = 29 | issue = 43 | pages = 13735–13741 | date = October 2009 | pmid = 19864586 | pmc = 2785708 | doi = 10.1523/JNEUROSCI.2547-09.2009 }}</ref> First, a selection operation that retrieves the most relevant item, and second an updating operation that changes the focus of attention made upon it. Updating the attentional focus has been found to involve the transient activation in the caudal [[superior frontal sulcus]] and [[posterior parietal cortex]], while increasing demands on selection selectively changes activation in the rostral superior frontal sulcus and posterior cingulate/[[precuneus]].<ref name="Bledowski" />

Articulating the differential function of brain regions involved in working memory is dependent on tasks able to distinguish these functions.<ref name="Coltheart-2006">{{cite journal | vauthors = Coltheart M | title = What has functional neuroimaging told us about the mind (so far)? | journal = Cortex; A Journal Devoted to the Study of the Nervous System and Behavior | volume = 42 | issue = 3 | pages = 323–331 | date = April 2006 | pmid = 16771037 | doi = 10.1016/S0010-9452(08)70358-7 | s2cid = 4485292 }}</ref> Most brain imaging studies of working memory have used recognition tasks such as delayed recognition of one or several stimuli, or the n-back task, in which each new stimulus in a long series must be compared to the one presented n steps back in the series. The advantage of recognition tasks is that they require minimal movement (just pressing one of two keys), making fixation of the head in the scanner easier. Experimental research and research on individual differences in working memory, however, has used largely recall tasks (e.g.,&nbsp;the [[reading span task]], see below). It is not clear to what degree recognition and recall tasks reflect the same processes and the same capacity limitations.

Brain imaging studies have been conducted with the reading span task or related tasks. Increased activation during these tasks was found in the PFC and, in several studies, also in the [[anterior cingulate cortex]] (ACC). People performing better on the task showed larger increase of activation in these areas, and their activation was correlated more over time, suggesting that their neural activity in these two areas was better coordinated, possibly due to stronger connectivity.<ref>{{cite journal | vauthors = Kondo H, Osaka N, Osaka M | title = Cooperation of the anterior cingulate cortex and dorsolateral prefrontal cortex for attention shifting | journal = NeuroImage | volume = 23 | issue = 2 | pages = 670–679 | date = October 2004 | pmid = 15488417 | doi = 10.1016/j.neuroimage.2004.06.014 | s2cid = 16979638 }}</ref><ref>{{cite journal | vauthors = Osaka N, Osaka M, Kondo H, Morishita M, Fukuyama H, Shibasaki H | title = The neural basis of executive function in working memory: an fMRI study based on individual differences | journal = NeuroImage | volume = 21 | issue = 2 | pages = 623–631 | date = February 2004 | pmid = 14980565 | doi = 10.1016/j.neuroimage.2003.09.069 | s2cid = 7195491 }}</ref>

=== Neural models ===
One approach to modeling the neurophysiology and the functioning of working memory is [[PBWM|prefrontal cortex basal ganglia working memory (PBWM)]]. In this model, the prefrontal cortex works hand-in-hand with the basal ganglia to accomplish the tasks of working memory. Many studies have shown this to be the case.<ref>{{cite journal | vauthors = Baier B, Karnath HO, Dieterich M, Birklein F, Heinze C, Müller NG | title = Keeping memory clear and stable—the contribution of human basal ganglia and prefrontal cortex to working memory | journal = The Journal of Neuroscience | volume = 30 | issue = 29 | pages = 9788–9792 | date = July 2010 | pmid = 20660261 | pmc = 6632833 | doi = 10.1523/jneurosci.1513-10.2010 | doi-access = free }}</ref> One used ablation techniques in patients who had had seizures and had damage to the prefrontal cortex and basal ganglia.<ref name=":2" /> Researchers found that such damage resulted in decreased capacity to carry out the executive function of working memory.<ref name=":2">{{cite journal | vauthors = Voytek B, Knight RT | title = Prefrontal cortex and basal ganglia contributions to visual working memory | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 42 | pages = 18167–18172 | date = October 2010 | pmid = 20921401 | pmc = 2964236 | doi = 10.1073/pnas.1007277107 | doi-access = free | bibcode = 2010PNAS..10718167V }}</ref> Additional research conducted on patients with brain alterations due to methamphetamine use found that training working memory increases volume in the basal ganglia.<ref>{{cite journal | vauthors = Brooks SJ, Burch KH, Maiorana SA, Cocolas E, Schioth HB, Nilsson EK, Kamaloodien K, Stein DJ | display-authors = 6 | title = Psychological intervention with working memory training increases basal ganglia volume: A VBM study of inpatient treatment for methamphetamine use | journal = NeuroImage. Clinical | volume = 12 | pages = 478–491 | date = 2016-02-01 | pmid = 27625988 | pmc = 5011179 | doi = 10.1016/j.nicl.2016.08.019 | doi-access = free }}</ref>

=== Effects of stress on neurophysiology ===
Working memory is [[effects of stress on memory|impaired by acute and chronic psychological stress]]. This phenomenon was first discovered in animal studies by Arnsten and colleagues,<ref>{{cite journal | vauthors = Arnsten AF | title = The biology of being frazzled | journal = Science | volume = 280 | issue = 5370 | pages = 1711–1712 | date = June 1998 | pmid = 9660710 | doi = 10.1126/science.280.5370.1711 | s2cid = 25842149 }}</ref> who have shown that stress-induced [[catecholamine]] release in PFC rapidly decreases PFC neuronal firing and impairs working memory performance through feedforward, intracellular signaling pathways that open potassium channels to rapidly weaken prefrontal network connections.<ref>{{cite journal | vauthors = Arnsten AF | title = Stress signalling pathways that impair prefrontal cortex structure and function | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 6 | pages = 410–422 | date = June 2009 | pmid = 19455173 | pmc = 2907136 | doi = 10.1038/nrn2648 }}</ref> This process of rapid changes in network strength is called Dynamic Network Connectivity,<ref>{{cite journal |last1=Arnsten |first1=Amy F.T. |last2=Paspalas |first2=Constantinos D. |last3=Gamo |first3=Nao J. |last4=Yang |first4=Yang |last5=Wang |first5=Min |title=Dynamic Network Connectivity: A new form of neuroplasticity |journal=Trends in Cognitive Sciences |date=August 2010 |volume=14 |issue=8 |pages=365–375 |doi=10.1016/j.tics.2010.05.003 |pmid=20554470 |pmc=2914830 }}</ref> and can be seen in human brain imaging when cortical functional connectivity rapidly changes in response to a stressor.<ref>{{cite journal |last1=Hermans |first1=Erno J. |last2=van Marle |first2=Hein J. F. |last3=Ossewaarde |first3=Lindsey |last4=Henckens |first4=Marloes J. A. G. |last5=Qin |first5=Shaozheng |last6=van Kesteren |first6=Marlieke T. R. |last7=Schoots |first7=Vincent C. |last8=Cousijn |first8=Helena |last9=Rijpkema |first9=Mark |last10=Oostenveld |first10=Robert |last11=Fernández |first11=Guillén |title=Stress-Related Noradrenergic Activity Prompts Large-Scale Neural Network Reconfiguration |journal=Science |date=25 November 2011 |volume=334 |issue=6059 |pages=1151–1153 |doi=10.1126/science.1209603 |pmid=22116887 |bibcode=2011Sci...334.1151H }}</ref> Exposure to chronic stress leads to more profound working memory deficits and additional architectural changes in PFC, including dendritic atrophy and spine loss,<ref>{{cite journal | vauthors = Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH | display-authors = 6 | title = Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex | journal = Cerebral Cortex | volume = 16 | issue = 3 | pages = 313–320 | date = March 2006 | pmid = 15901656 | doi = 10.1093/cercor/bhi104 | doi-access = free }}</ref> which can be prevented by inhibition of protein kinase C signaling.<ref>{{cite journal | vauthors = Hains AB, Vu MA, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AF | title = Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 42 | pages = 17957–17962 | date = October 2009 | pmid = 19805148 | pmc = 2742406 | doi = 10.1073/pnas.0908563106 | doi-access = free | bibcode = 2009PNAS..10617957H | author-link4 = Christopher H. van Dyck }}</ref> [[fMRI]] research has extended this research to humans, and confirms that reduced working memory caused by acute stress links to reduced activation of the PFC, and stress increased levels of [[catecholamine]]s.<ref>{{cite journal | vauthors = Qin S, Hermans EJ, van Marle HJ, Luo J, Fernández G | title = Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex | journal = Biological Psychiatry | volume = 66 | issue = 1 | pages = 25–32 | date = July 2009 | pmid = 19403118 | doi = 10.1016/j.biopsych.2009.03.006 | s2cid = 22601360 }}</ref> Imaging studies of medical students undergoing stressful exams have also shown weakened PFC functional connectivity, consistent with the animal studies.<ref>{{cite journal | vauthors = Liston C, McEwen BS, Casey BJ | title = Psychosocial stress reversibly disrupts prefrontal processing and attentional control | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 3 | pages = 912–917 | date = January 2009 | pmid = 19139412 | pmc = 2621252 | doi = 10.1073/pnas.0807041106 | doi-access = free | bibcode = 2009PNAS..106..912L }}</ref> The marked effects of stress on PFC structure and function may help to explain how stress can cause or exacerbate mental illness.
The more stress in one's life, the lower the efficiency of working memory in performing simple cognitive tasks. Students who performed exercises that reduced the intrusion of negative thoughts showed an increase in their working memory capacity. Mood states (positive or negative) can have an influence on the neurotransmitter dopamine, which in turn can affect problem solving.<ref>{{cite book| vauthors = Revlin R |title=Human Cognition : Theory and Practice.|year=2007|publisher=Worth Pub|location=New York, NY|isbn=978-0-7167-5667-5|page=147|edition=International}}</ref>

=== Effects of alcohol on neurophysiology ===
Excessive alcohol use can result in brain damage which impairs working memory.<ref name="pmid21466500">{{cite journal | vauthors = van Holst RJ, Schilt T | title = Drug-related decrease in neuropsychological functions of abstinent drug users | journal = Current Drug Abuse Reviews | volume = 4 | issue = 1 | pages = 42–56 | date = March 2011 | pmid = 21466500 | doi = 10.2174/1874473711104010042 }}</ref> Alcohol has an effect on the [[Blood-oxygen-level dependent|blood-oxygen-level-dependent]] (BOLD) response. The BOLD response correlates increased blood oxygenation with brain activity, which makes this response a useful tool for measuring neuronal activity.<ref>{{cite journal | vauthors = Jacobus J, Tapert SF | title = Neurotoxic effects of alcohol in adolescence | journal = Annual Review of Clinical Psychology | volume = 9 | issue = 1 | pages = 703–721 | year = 2013 | pmid = 23245341 | pmc = 3873326 | doi = 10.1146/annurev-clinpsy-050212-185610 }}</ref> The BOLD response affects regions of the brain such as the basal ganglia and thalamus when performing a working memory task. Adolescents who start drinking at a young age show a decreased BOLD response in these brain regions.<ref>{{cite journal | vauthors = Weiland BJ, Nigg JT, Welsh RC, Yau WY, Zubieta JK, Zucker RA, Heitzeg MM | title = Resiliency in adolescents at high risk for substance abuse: flexible adaptation via subthalamic nucleus and linkage to drinking and drug use in early adulthood | journal = Alcoholism: Clinical and Experimental Research | volume = 36 | issue = 8 | pages = 1355–1364 | date = August 2012 | pmid = 22587751 | pmc = 3412943 | doi = 10.1111/j.1530-0277.2012.01741.x }}</ref> Alcohol dependent young women in particular exhibit less of a BOLD response in parietal and frontal cortices when performing a spatial working memory task.<ref>{{cite journal | vauthors = Tapert SF, Brown GG, Kindermann SS, Cheung EH, Frank LR, Brown SA | title = fMRI measurement of brain dysfunction in alcohol-dependent young women | journal = Alcoholism: Clinical and Experimental Research | volume = 25 | issue = 2 | pages = 236–245 | date = February 2001 | pmid = 11236838 | doi = 10.1111/j.1530-0277.2001.tb02204.x }}</ref> Binge drinking, specifically, can also affect one's performance on working memory tasks, particularly visual working memory.<ref>{{cite journal | vauthors = Ferrett HL, Carey PD, Thomas KG, Tapert SF, Fein G | title = Neuropsychological performance of South African treatment-naïve adolescents with alcohol dependence | journal = Drug and Alcohol Dependence | volume = 110 | issue = 1–2 | pages = 8–14 | date = July 2010 | pmid = 20227839 | pmc = 4456395 | doi = 10.1016/j.drugalcdep.2010.01.019 }}</ref><ref>{{cite journal | vauthors = Crego A, Holguín SR, Parada M, Mota N, Corral M, Cadaveira F | title = Binge drinking affects attentional and visual working memory processing in young university students | journal = Alcoholism: Clinical and Experimental Research | volume = 33 | issue = 11 | pages = 1870–1879 | date = November 2009 | pmid = 19673739 | doi = 10.1111/j.1530-0277.2009.01025.x | hdl-access = free | hdl = 10347/16832 }}</ref> Additionally, there seems to be a gender difference in regards to how alcohol affects working memory. While women perform better on verbal working memory tasks after consuming alcohol compared to men, they appear to perform worse on spatial working memory tasks as indicated by less brain activity.<ref>{{cite journal | vauthors = Greenstein JE, Kassel JD, Wardle MC, Veilleux JC, Evatt DP, Heinz AJ, Roesch LL, Braun AR, Yates MC | display-authors = 6 | title = The separate and combined effects of nicotine and alcohol on working memory capacity in nonabstinent smokers | journal = Experimental and Clinical Psychopharmacology | volume = 18 | issue = 2 | pages = 120–128 | date = April 2010 | pmid = 20384423 | doi = 10.1037/a0018782 }}</ref><ref>{{cite journal | vauthors = Squeglia LM, Schweinsburg AD, Pulido C, Tapert SF | title = Adolescent binge drinking linked to abnormal spatial working memory brain activation: differential gender effects | journal = Alcoholism: Clinical and Experimental Research | volume = 35 | issue = 10 | pages = 1831–1841 | date = October 2011 | pmid = 21762178 | pmc = 3183294 | doi = 10.1111/j.1530-0277.2011.01527.x }}</ref> Finally, age seems to be an additional factor. Older adults are more susceptible than others to the [[Effects of alcohol on memory|effects of alcohol on working memory]].<ref>{{cite journal | vauthors = Boissoneault J, Sklar A, Prather R, Nixon SJ | title = Acute effects of moderate alcohol on psychomotor, set shifting, and working memory function in older and younger social drinkers | journal = Journal of Studies on Alcohol and Drugs | volume = 75 | issue = 5 | pages = 870–879 | date = September 2014 | pmid = 25208205 | pmc = 4161706 | doi = 10.15288/jsad.2014.75.870 }}</ref>