Neuroanatomy and Physiology of Cognition​

Larry Culpepper, MD, MPH

From the Department of Family Medicine, Boston University School of Medicine, Boston, Massachusetts

Research into the neuroanatomy and physiology of cognition is a rapidly expanding field of knowledge with applications for the treatment of MDD and other psychiatric conditions.1 Early cognition research came from animal studies and studies of patients with brain lesions, but imaging technology has provided more details on how the brain thinks and works. Refined imaging techniques, novel testing, and analytic strategies for cognitive paradigms (eg, executive function, negative bias, memory) now support major advances in conceptualizing brain function. Cognitive processes that were once considered to be based in specific brain areas are now understood to be highly complex, resulting from interconnections involving multiple areas of the brain.2

A key recent advance is in understanding the functions and interrelationships between 3 brain networks: the central executive network (CEN), the salience network (SN), and the default mode network (DMN) (Table 1).3,4 Alterations in these networks manifest in the symptoms that contribute to psychiatric disorders such as MDD.5 The underlying changes also manifest in cognitive deficits that may not be as evident to the clinician. For many patients, these deficits and the underlying network alterations are present before symptoms develop and can be detected between symptomatic episodes, suggesting that they are core processes in the development of MDD rather than being produced by the symptoms.

Cognitive Functions Affected by MDD

Cognitive functions may be described as either hot (emotion-laden) or cold (emotion-independent for the most part).6 For individuals with MDD, the most replicable areas of cognitive impairment are evident in cold cognitive domains of executive function, attention, working memory, and psychomotor processing.7 In addition to these impairments, depression is associated with negative bias, a dysfunction of hot cognition.1,6 Negative bias, hypothesized to be a core source of major depressive syndromes, is a negatively valenced perception of and response to the environment.1 Patients with depression show a greater negative interpretation of sensory inputs and experiences, increased attention to and focus on negative information, decreased attention to positive information, and more difficulty inhibiting negative processing compared with healthy controls.6

Discovering more about the brain’s function and the neural networks involved in various affective and cognitive functions may provide new treatment targets for the mood and cognitive symptoms associated with MDD.

Cognitive Processes

At its core, the brain is tasked with being aware of and responding to the environment. The human environment includes the external physical world, the internal state, and the social world. The brain has to perceive the environment, survey it, and monitor it for changes, which involves cognitive processes devoted to the control, focus, and filtering of sensory information. The brain has to interpret and appraise this sensory input and identify changes occurring in the environment. This process involves memory to compare the present environment with the past environment. The brain must store, retrieve, and process information using both short- and long-term memory, including sensory memories.

When changes in the environment are perceived, the brain has to evaluate their significance (salience) and prepare responses with the goal of minimizing threats and maximizing rewards. In addition, the brain must maintain an internal representation of other current goals and modulate actions toward their achievement. This cognitive activity has both a mental component and a bodily preparation component. The mental component involves a switch from the DMN, which is engaged when nothing unusual is occurring, to the engagement of the CEN and activation of executive functions. Bodily preparation involves connections from the CEN, SN, DMN, and other cortical and higher brain regions to the basal ganglia, hypothalamus, midbrain, and other regions that enable communication with and control of other organs and body systems.

Core Networks

The 2 cognitive control networks, the CEN and SN, work in balance with the DMN, and the 3 together control much of the interaction of the human organism with its environment.8,9 The DMN is normally active when there are no demands on the brain to respond to its environment. It is also active with introspection and autobiographical memory activity and may be related to creativity.3 In depressed individuals, this network also plays a role in rumination related to negative content. The SN and its connections to the DMN and CEN provide the mechanism by which the brain evaluates the salience of events, identifies those requiring nonautomatic response, and activates the CEN to provide executive control to the organism’s response.4 Concomitant with engagement of the SN and CEN, the DMN deactivates. Deficits may occur in this switching, in the level of activity of the brain regions involved in these networks as well as in the connectivity between components within and between networks. These deficits can result in lapses in attention and other cognitive problems, including executive functions.

Broad inefficiency in executive functions exists in MDD, including inhibition, sustained attention, working memory, and task shifting associated with failure to activate or hypoactivity of the SN and CEN or failure to deactivate the DMN when the SN and CEN activate. For individuals with depression, fMRI evidence10,11 shows increased cortical activation on some cognitive tests, which indicates that they are working harder than healthy control participants to complete the same task. One recent meta-analysis12 found that these disruptions persist whether depressive symptoms are present or not.


Other Brain Areas Interacting with Cognitive Processes

The cognitive impairments associated with depression are influenced by both bottom-up and top-down neural connections.6 In the brain, bottom-up mechanisms derive from changes in the midbrain and lower brain regions (basal ganglia, striatum, thalamus), which are then transmitted to higher brain regions. Top-down processes originate in the cortical prefrontal, temporal, and parietal lobe sources and are transmitted to lower brain regions.

With both bottom-up and top-down signaling, the hippocampus and the amygdala are critical intermediary midbrain regions of the temporal lobe. The prefrontal cortex signals directly down to the basal ganglia and lower regions as well as to the hippocampus and amygdala. The lower brain regions similarly have strong connections to the hippocampus and the amygdala, and they also project directly up to the cortical regions involved in cognition.6

The hippocampus is critical to learning, memory, and the integration of emotion and cognition. Problems with concentration, memory, and decision-making are common in patients with MDD and may be accompanied by abnormalities in the hippocampus and prefrontal cortex.13 Abnormal hippocampal activation in patients with depression as demonstrated by fMRI studies indicates that this area is susceptible to changes throughout the course of MDD.14 Reduced hippocampal activity in patients with MDD compared with never-depressed control subjects affects memory14 and produces negative bias.15

The amygdala is another key midbrain hub in the perception and interpretation of stimuli. It has extensive connectivity with other brain regions that are central to interactions between cognition and emotion (AV 1).1,16 Emotional regulation includes both explicit and implicit regulation. The former requires deliberate and effortful cognitive processing and involves activation of the CEN and SN along with decreasing activity in the amygdala.17 Implicit regulation does not require activation of the 2 cognitive control networks but does involve decreasing amygdala activity. Failure to inhibit or sustain inhibition of amygdala activity, including through decreased connectivity between the prefrontal cortex and amygdala, contributes to the negative bias prevalent in depression.1,18

AV 1. Amygdala Functions (00:23)

Based on Pessoa16

Altered Neurotransmitters and Other Alterations Influencing Cognition in Depression

Multiple neurotransmitter systems (such as serotonin, dopamine, and norepinephrine) are involved in signaling within and between regions of the brain involved in cognition.13 Prefrontal cortex regions involved in the cognitive control networks also have top-down connections to the cell bodies in the brain stem from which monoamines originate.19 In depressed individuals, deficient top-down cold cognitive control and negative bottom-up perceptions and expectations result from abnormal monoamine transmission and lead to negative patterns of thought and behavior (AV 2).6 Serotonin, which originates mostly in the raphe nuclei, affects upper cognitive brain regions. A PET imaging study20 found that the 5-HT1A receptor binding potential was reduced by 42% in the raphe nuclei in subjects with depression compared with healthy control subjects. Norepinephrine originates in the locus coeruleus and has a diverse projection to higher regions that alter forebrain activities such as attention, perception, and memory.21,22 Dopamine neurons located in the ventral tegmental area with substantia nigra project to the nucleus accumbens and prefrontal cortex and alter reward response.23 In MDD, altered glutamate activity is involved in the activation and switching of the SN and CEN networks and in deactivation of the DMN.24

AV 2. Hot and Cold Cognition Processes in Healthy and Depressed Individuals (01:09)

Based on Roiser and Sahakian6
Abbreviations: 5-HT = serotonin, A = amygdala, ACC = anterior cingulate cortex, DA = dopamine, DLPFC = dorsolateral prefrontal cortex, H = hippocampus, NA = nucleus accumbens, NE = norepinephrine

Depression is also associated with decreased neurogenesis and increased destruction at the cellular level of neuron and glia production and dendritic and synaptic proliferation. These processes may be influenced by or contribute to other alterations that contribute to cognitive changes, such as hormonal alterations, inflammatory changes, oxidative stress, and production of brain-derived neurotrophic factor.25,26

Finally, cognitive impairment may also be influenced by genetic and epigenetic changes, including those related to early life experiences and trauma.27 For example, prolonged stress response due to traumatic events during childhood may alter various brain regions and affect cognitive processes including mental flexibility and memory in adulthood.27 The degree of cognitive impairment may also be influenced by factors such as prior history of depression, anxiety and other psychiatric conditions, and early life experiences.

Cognitive changes have been shown to improve in some patients as depressive symptoms improve, likely due to the connections between mood and emotional processes in the brain.28,29 However, a substantial portion of patients continue to experience very significant cognitive impairment even when euthymic. A need remains for increased understanding of the cerebral circuits underpinning cognitive function and for specific treatments that target cognitive symptoms and negative thought processes.30


In patients with MDD, the most common cognitive impairments are related to executive function, memory, attention, and processing speed. A bias toward negative stimuli also affects how patients with MDD perceive and respond to their environment, which includes external, internal, and social input. Based on data from improved imaging technology, many cognitive functions once assumed to be localized in specific areas of the brain now appear to result from interconnectivity of complex neural networks. Both top-down and bottom-up mechanisms in the brain are involved in cognitive changes and depressive symptoms. Altered monoamine neurotransmission is implicated in negative bias, depressive symptoms, and an elevated response to perceived failures. Serotonin, norepinephrine, and dopamine transmission is affected along key networks and in key hubs. Cognitive deficits frequently persist between symptomatic episodes of depression in spite of otherwise effective treatment. New treatments are needed for cognitive symptoms that hinder patients’ return to full functioning.

Clinical Points

  • Recognize common cognitive symptoms and negative bias in your patients with MDD
  • Understand current knowledge of how disrupted connections in the central executive network, salience network, and default mode network along various top-down and bottom-up brain connections contribute to problems in executive function, memory, attention, and processing speed
  • Realize that current treatments do not address specific areas of cognitive impairment, such as negative thought processes, which often occur in patients with MDD


5-HT = serotonin

CEN = central executive network

DMN = default mode network

fMRI = functional magnetic resonance imaging

MDD = major depressive disorder

PET = positron emission tomography

SN = salience network

Take the online posttest.


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