Stress, Neural Plasticity, and Major Depression

Serge Campeau, PhD

Premiere Date: December 20, 2017
Expiration Date: June 20, 2019

This activity offers CE credits for:

1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To understand the role of stress in the manifestation of depressive symptoms.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

• Describe the brain circuits associated with depressive symptom clusters

• Identify the multiple functions associated with reward systems (eg, anticipatory, consummatory)

• Explain how the frontal cortex affects cognition in depression

TARGET AUDIENCE

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

CREDIT INFORMATION

CME Credit (Physicians):This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™.

DISCLOSURE DECLARATION

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The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Serge Campeau, PhD, has no disclosures to report.

Bruce S. McEwen, PhD, (peer/content reviewer) has no disclosures to report.

Applicable Psychiatric Times staff and CME Outfitters staff have no disclosures to report.

UNLABELED USE DISCLOSURE

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

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Everyone experiences psychological stressors daily, which elicit relatively stereotypical and coordinated cognitive, behavioral, autonomic, and neuroendocrine responses orchestrated by the brain. These reactions are adapted to counter real or perceived threatening situations that normally safeguard individuals by maintaining or restoring physiological homeostasis. However, these adaptive reactions, when prolonged, chronic, or traumatic, come at physiological and metabolic costs and induce long-term neuroplastic modifications that are frequently linked with several psychopathologies, including MDD.

The sustained activation and neuroplasticity within and between multiple neural networks engendered by perceived stress are known to modify mood and affect, the experience of pleasure, cognition, somatic functions and, ultimately, survival. Advances in the neurosciences continue to elucidate the ways in which specific brain networks, together with several other organs, respond to stressful situations, and how these initially adaptive modifications progressively lead to clinical pathological states.

Although much work is still needed to achieve a more complete understanding of the mechanisms responsible for depressive disorder, progress in distinguishing symptom clusters, structural/functional modifications in associated brain networks, and innate genetic and epigenetic contributions, has shed light on this condition, which commands such high human and financial costs. This improved knowledge translates into more effective and targeted treatment approaches.

Continuing efforts in the nosology of major depression emphasize different symptom categories or endophenotypes that are intimately associated with the functions of distinct brain regions and networks. In a recent analysis, the 9 criteria for major depressive episodes from DSM-IV-TR (not considerably modified in DSM-5) were clustered into 4 “clinical content” subtypes of depression, including¹:

• Depressed mood

• Anhedonic depression

• Cognitive depression

• Somatic depression

Given the symptom variability upon presentation of a depressive disorder, an important question is the extent to which these content clusters and their underlying circuits are differentially regulated by stress. The following provides a description of how stress influences brain structures and functions, as they pertain to different symptom categories of MDD.

Prefrontal cortex, amygdala, hippocampus, and depressed mood

Prefrontal cortical networks have been linked to psychopathologies, including MDD. Human imaging studies suggest that modifications of functional prefrontal network activities and connectivities with the parietal cortex, amygdaloid, and hippocampal formations are intimately related to the depressed mood cluster, one of the two defining symptoms of major depression.²

A relatively stable account of functional brain alterations in major depression includes hypoactivity of the dorsolateral prefrontal cortex with reduced functional connectivity with the posterior parietal cortex and hippocampal formation. This functional outcome is often concurrent with hyperactivity in the ventromedial prefrontal and lateral orbitofrontal regions. The prominence of negative valuation of the self/environment is correlated with hyperactivity in the medial prefrontal/orbitofrontal cortex network linked with the amygdala. Supporting anatomical and morphological evidence for structural modifications of prefrontal, amygdala, and hippocampal subregions in clinical depression indicates changes in regional volumes (gray matter), neural/glial cell numbers, neurogenesis, and cortical thickness, which are correlated with severity of mood symptoms.³

As one of several etiologic factors, stress is a leading candidate related to the presentation of major depression. In agreement with epidemiological studies, laboratory studies in humans indicate that acute stress increases indices of negative mood while simultaneously reducing positive affect-outcomes that normally subside within 24 hours.⁴ An important question related to these findings is whether repeated stress is a necessary antecedent to eventually yield a diagnosis of major depression.

Whereas controlled chronic stress studies in humans do not appear to have been performed with precise mood determination, the outcome of major traumatic events such as the 9/11 US terrorist attacks or major earthquakes in China are suggestive of long-term functional and/or volumetric modifications in the prefrontal-amygdala-hippocampal networks.^5,6 The results of these studies are quite variable, however, at times highlighting different functional network alterations compared with major depression.

Morphometric studies in laboratory animals invariably link stress with structural modifications in pyramidal neurons of the anterior cingulate, prelimbic, and infralimbic cortices, and hippocampal formation, which comprise reduced dendritic length, branching, spine densities, and reduced neurogenesis in the hippocampal dentate gyrus.³ Importantly, stress concurrently induces dendritic hypertrophy in specific amygdala subdivisions and in the lateral orbitofrontal cortex-modifications that can become visible after a single stress episode. As a whole, this research suggests that diverse modalities of stress differentially influence discrete affective processes, and their underlying prefrontal, amygdala, and hippocampal networks. Keep in mind also that sex differences in multiple cognitive and affective abilities are observed in response to stress in humans and animals. Moreover, for several functions, distinct brain networks are recruited in women and men, which perhaps contribute to the differential susceptibility of these networks and associated functions across the sexes.

The exact signals necessary to induce stress-related structural modifications are still under intense scrutiny. Multiple neurotransmitter, hormonal, and intracellular signals have been studied in association with stress and depressive disorders. Stress consistently alters serotonergic, noradrenergic, and dopaminergic neurotransmission that modulates animal anxiety-like behaviors (social interactions, innate fears, learned fears, and their extinction). Likewise, experimentally induced excesses or deficiencies in these neurotransmitter systems within the prefrontal networks contribute to structural, functional, and anxiety-like alterations.

Although these systems have provided the main pharmacological targets of antidepressant treatments ever since the original serotonin/noradrenaline depletion hypothesis of depression, the overall effect size of typical antidepressant drugs compared with placebo effects has been relatively small. This is not to say, however, that serotonin and noradrenaline do not contribute to the development or maintenance of some depressive symptoms, as there are indications that drug treatments can quickly ameliorate cognitive functions in depressed patients while producing no immediate effects on ratings of mood or anxiety.

Glucocorticoids, one of the key hormones rising during acute stress and often dysregulated in chronic stress conditions, can mimic the effects of chronic stress when given exogenously and repeatedly. Glucocorticoid receptor interference during chronic stress can prevent dendritic remodeling and ensuing anxiety-like behaviors. The role of glucocorticoids and their receptors is best demonstrated in major depression with psychotic features, but much less so in psychosis-free depression.⁷

The broad role of glutamate neurotransmission in neuroplasticity and the effects of stress and antidepressant actions has recently received much attention. Subanesthetic ketamine was found to reduce mood symptoms within hours of injection in treatment-resistant depressed patients.⁸ Amelioration of both mood and cognitive functions following ketamine administration is associated with normalization of prefrontal network activity, a finding mirrored in a number of animal studies that investigated stress-induced prefrontal cortex neural plasticity.^9,10 These latest studies appear to provide a breakthrough in the availability of new evidence-based treatment options for major depression.

Nucleus accumbens, ventral tegmental area, and anhedonic depression

Anhedonia makes up the second of the 2 main core symptoms of major depression. Multiple functions are associated with reward systems, including distinctions between anticipatory versus consummatory reward (ie, wanting versus liking properties of reward), the learning of cue-reward versus action-reward contingencies and predictions, and effort-reward relationships. The brain circuits most closely associated with reward functions include the ventral tegmental area, the ventral striatum/nucleus accumbens, dorsal striatum, putamen, and medial prefrontal/orbitofrontal and anterior cingulate cortices.

Recent imaging studies in depressed patients indicate functional differences in the ventral striatum/nucleus accumbens, ventral tegmental area, and medial prefrontal cortex, especially in response to reward anticipation, cue- and action-reward learning, and the processing of effort/reward ratios.¹¹ Depressed patients often display hypoactivity in these regions, although hyperactivity has been reported under some conditions. However, anhedonia is not limited to major depression, as it is common in schizophrenia, drug addiction, and other psychiatric conditions. These results have led some investigators to speculate that reward and reinforcement functions are susceptible trait factors that contribute to the presentation of multiple psychiatric conditions, including MDD.

The capacity of acute and chronic stress to modulate activity at the level of the ventral tegmental area, nucleus accumbens, and medial prefrontal/orbital cortex has received some attention in human studies. Whereas acute stress is frequently reported to increase anticipatory reward, it simultaneously blunts consummatory responses, with attendant increases (anticipatory) and decreases (liking) in striatal activity.¹² The normally biased action-reward learning is also reduced when preceded by an acute stressor.

Controlled chronic stress studies in humans are not available, but findings from retrospective studies of abused populations, especially during childhood, indicate reduced activity in some striatal regions, especially in response to reward-related cues but not to negative or neutral stimuli.¹¹ Implicit in these findings is the realization that “anhedonia” is far from a unitary construct, with different reward-related functions employing distinct molecular and circuit components. Some of these differences may signify diverse pathophysiological pathways in the causes of MDD. Exactly how increased anticipatory responses initially triggered by acute stress are instead reduced following chronic or traumatic stress experiences is still unknown.

The differential acute stress effects frequently reported to anticipatory versus consummatory reward functions are mediated by different neurotransmitter systems. Anticipatory reward is largely dependent on increased dopaminergic functions of the mesostriatal system without significantly modifying the “pleasantness” (liking property) of rewards. On the other hand, hedonic or consummatory properties of many rewards are closely associated with endogenous opiates and endocannabinoid activity. Anatomical and functional animal studies of the ventral striatum/nucleus accumbens regions further indicate key additional GABAergic and glutamatergic afferent regulation from the thalamus, hippocampus, amygdala, and prefrontal regions.

Recent neurotechnologies are providing refinements in understanding the synaptic remodeling induced by repeated stress in these reward-related regions. Many of the same signals discussed in the context of depressed mood symptoms contribute to the presentation of stress-induced anhedonia, including dopamine, norepinephrine, glucocorticoids and, more recently, inflammatory molecules and glutamate. Surprisingly, dopamine system manipulations in major depression generally do not improve depressive or anhedonic symptoms with any consistency, or beyond other traditional pharmacologic interventions.

There is a sense that patients who display stronger anhedonic characteristics make up a higher percentage of those with treatment-resistant major depression. In this regard, the recent development of subanesthetic ketamine administration also reduces anhedonic symptoms, which may account for its improved effectiveness in treatment-refractory patients. Perhaps this approach will provide more effective treatment of anhedonic symptoms and other negative symptoms associated with depression and schizophrenia that traditionally have been treatment-refractory.

Frontal cortex and cognitive depression

Multiple cognitive abilities broadly associated with frontocortical executive functions are altered in MDD. Indeed, major depression is frequently associated with deficits in selective attention, vigilance, short-term and working memory, decision-making, inhibitory control, cognitive flexibility, and information-processing speed. Multiple imaging studies report alterations of functional prefrontal cortical network activities and connectivities correlated with depressed cognitive functions.² Hypoactivity of the dorsolateral prefrontal cortical network, and its associated reduced functional connectivity with the posterior parietal cortex and hippocampal formation, easily map onto the attentional and memory disruptions observed in major depression.

The clear disambiguation of the role of specific prefrontal regions in mood versus cognitive functions and associated symptoms awaits the development of more refined imaging techniques. Furthermore, it is not clear whether mood and cognitive symptoms generally precede or follow one another, although the suggestion that prodromal cognitive biases induce depressed mood has been entertained.¹

Chronic stress modifies decision-making in humans by shifting goal-directed decisions to more “habitual” actions/decisions, which is associated with volume reductions in prefrontal network subregions-changes that are reversible upon withdrawal from the stressful environment. Chronic stress, however, is not necessary to induce cognitive dysfunction, since acute mild stressors consistently disrupt working memory and attention functions, which are closely associated with prefrontal networks. Repeated stress impairs flexibility on attentional set-shifting and reversal learning tasks.

An emerging consensus from studies of clinically depressed patients is that while monoamine therapy can influence the symptoms of depression, it is frequently insufficient to cure the underlying pathophysiological condition, which appears increasingly linked to glutamatergic neurotransmission.⁸

The brainstem, hypothalamus, and somatic depression

Depressed patients frequently display multiple somatic symptoms that present as excesses or deficiencies such as excessive sleep or insomnia (and associated thermoregulatory indices), significant weight gain or loss (and associated metabolic/hormonal indices), general fatigue/lack of energy, and changes in motoric/behavioral activities. These functions are most proximally regulated by subcortical regions centered in different brainstem and hypothalamic nuclei-deep brain regions that are typically difficult to observe in human functional imaging studies.

Recent imaging studies reveal correlations between BMI and cortical gray volume modifications in the same prefrontal regions found abnormal in depressed patients.¹³ Sleep deprivation is also known to induce prodromal mood and cognitive dysfunctions in control subjects, changes that correlate with robust modifications of brain functional connectivity, comparable to the patterns observed in depression. Factors such as sleep and body weight dysregulation have been argued to provide distinct causative pathways to depression, given their independent risk status in the presentation of major depression.

Recent attempts at integrating these somatic dysregulations with mood and anhedonic symptoms have proposed a general disruption in interoceptive signal processing as a main disease process potentially underlying depressive symptom presentation.¹⁴ Although promising, much work remains to be done to assess this “bottom-up” somatic processing disruption hypothesis.

Acute and chronic stress exposure are frequently associated with somatic dysregulation. Although mostly unexplored in humans, cortical influences arising from specific prefrontal regions have been traced to multiple brainstem and hypothalamic targets directly responsible for the regulation of somatic functions.³ In the context of weight regulation, both human and animal studies indicate the anorectic actions of acute stress but variable effects with chronic stress.¹⁵

Many of the above-mentioned somatic symptoms can present during infections, a state defined as “sickness behavior.”¹⁶ This state is induced by activation of peripheral innate immune cells that release proinflammatory cytokines, which influence different hypothalamic and brainstem regions through vagal and humoral mediated signals. How this network is “hijacked” into full-blown depressive disorder is currently unclear, as is suggested from clinical populations treated with some forms of cytokines. In addition, brainstem neurotransmitters have been implicated in the regulation of somatic functions that interact with most of the signals discussed in the context of depressed mood, anhedonia, and cognition. Through mechanisms that have yet to be identified, somatic symptoms generally improve when depressive symptoms subside.

Conclusion

Based on accruing empirical evidence, there is no doubt that stress-no matter how contrived conceptually-bears a strong association with MDD. Stress demonstrably influences multiple brain regions and their functions simultaneously, across all the main symptom clusters of major depression. The correlation between structural and functional modifications is generally high, but unambiguous causal relationships still require evaluations, especially between symptom clusters. It is also apparent that there are multiple causes of the depressive symptoms and that although likely accounting for symptom variability, these distinct pathways influence key structures and functions. Multiple genetic, epigenetic, sex, and experiential factors readily interact to account for variable susceptibilities to stress, and the consequent development of depressive symptoms.

Furthermore, the multiple molecular signals traditionally linked to major depression are likely to contribute to brain/network modifications. The glutamatergic interventions that use ketamine appear to be closely associated with these network modifications; they provide faster and widespread symptom improvements compared with most traditional pharmacologic interventions. However, this approach alone has not proved curative. Therefore, the extent to which different affective, hedonic, cognitive, and somatic functions are modified by stress, and how these neuroadaptations are maintained and possibly reversed, should remain top research priorities.

CME POST-TEST

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Disclosures:

Dr. Campeau is Professor, Department of Psychology and Neuroscience, Director, Interdepartmental Neuroscience PhD Program, University of Colorado Boulder, Boulder, CO.

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