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The Threat Neurocircuitry That Underlies Depression and Anxiety

New neuroimaging research dissects common pathways.

Key points

  • Depression and anxiety present in diverse ways, making diagnosis and treatment challenging.
  • Transdiagnostic and neuroscience-based models present the promise of identifying the key levers, the final common pathways, to improve care.
  • Research suggests that how fear-based responses are learned and unlearned is a key factor in anxiety, depression, and trauma.
  • Neuroscience-guided care is more likely to produce targeted and swift clinical results as understanding improves.

By Grant H. Brenner

In order to deeply understand how something really works, to most effectively intervene to produce reliable, positive outcomes, we need to understand the “final common pathways” – we need to know where the levers are to figure out which ones to pull. We're not there yet, but progress is vigorous, and cutting-edge treatments are becoming increasingly available.

Transdiagnostic Models and the Brain

Neuroscience and psychiatry are early-on in understanding basic science and clinical application, rendering “transdiagnostic models” of particular importance because they show us what's going on under the hood. For example, research suggests that “dysconnectivity” in adolescent brains – problematic connectivity patterns in the brain’s “connectome” – underlies a predisposition to many different psychiatric conditions via ancient brain structures underlying signaling.

Clinically, we use the terms “depression” and “anxiety” to refer to a wide variety of conditions and presentations. For example, some with depression experience low energy, increased tiredness and sleep, or low appetite. In contrast, others are activated and irritable, eat to excess, while tired, are unable to get any rest, and so on with many other variations.

Similarly, with anxiety, some people experience physical symptoms. In contrast, anxiety is mainly mental for others, and some experience acute anxiety to the point of panic while others a deep sense of vague, overwhelming unease.

Indeed, while "depression" is represented as a singular diagnosis with subtypes, research suggests that on the level of brain circuitry, there are four distinct "biotypes" of depression, which may require different clinical approaches. What might all these presentations have in common?

Is Threat Processing a Final Common Pathway in Anxiety and Depression?

Along these lines, research published in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging (2022) looks closely at fear learning and unlearning in the brain and how that relates to future risk of depression.

In prior research, the study authors pointed to the role of how threat cues are processed, also called “fear conditioning.” Fear conditioning underlies stress-related disorders, notably posttraumatic stress disorder (PTSD), which may overlap with depression, in which abnormal fear conditioning leads to both intrusive thoughts, memories, and nightmares (“re-experiencing symptoms”), avoidance and emotional numbing, and hyperarousal symptoms including panic, anger, and difficulty with clear thinking and mood (cognitive and depressive symptoms).

There are three phases of fear conditioning: acquisition, when the fear is learned; extinction, when the fear reaction fades away; and extinction recall, the awareness of the conditioning process. This type of conditioning is based on the familiar model of Pavlov’s dogs. First, our furry friends are presented with a paired stimulus of food (the unconditioned, natural response) and the sound of a bell (the conditioned response), leading them to salivate when they hear the bell even without food. If the bell is rung without food, the salivation response still takes place.

However, unless from time to time food and bell are presented together, the dogs eventually stop salivating to the bell alone as the conditioned responses weaken, and disappears (extinction). This unlearning process is critical to prevent fear reactions from persisting after then are no longer required for for optimal function, even survival.

Hence, when extinction fails, if the sense of threat persists even when the danger has passed, it can underpin clinically-significant distress. In experiments like this one, participants receive a mild but painful electrical shock, and researchers look at how the shock (the unconditioned response) gets paired with the reaction and how that fades away – notably, extinction recall, the way things appear to us looking back, is a key factor. Whether a threatening, even traumatic, event lodges in memory and causes problems later, or gets placed into a workable context and becomes a part of our self-narrative, makes all the difference in the world.

Researchers recruited 279 young adults to look at how anxiety, depression, and threat were related. About 150 completed all phases of the study over thirty months of transition from late adolescence to early adulthood.

They completed measures of anxiety and depression, including the Fear Survey Schedule, the Albany Panic and Phobia Questionnaire, the Self-Consciousness subscale of the Social Phobia Scale, the Inventory to Diagnose Depression, the Mood and Anxiety Symptom Questionnaire, the Penn State Worry Questionnaire, and the Obsessive-Compulsive Inventory-Revised. Based on prior research, analysis was focused on dimensions of general distress, fears, and anhedonia-apprehension (anhedonia is the inability to experience pleasure or enjoy activities).

Participants, during brain scanning to identify real-time activity (“functional MRI” or magnetic resonance imaging), completed a fear acquisition, extinction, and extinction-recall conditions, with analysis of brain activity in key ROIs ("regions of interest")1 to seek correlations with brain activity and future depression and anxiety.

When It's Difficult to Tell Threatening From Safe Situations

There were two major findings from this study regarding neural responsiveness in various fear-conditioning phases. Participants whose brain circuits had trouble distinguishing the actual fear from the conditioned response during fear acquisition showed greater overall clinical increases in fear over the next 30 months. This was true in all brain regions studied, strongest in the ventromedial prefrontal cortex (vmPFC), an area of the brain involved with emotion regulation, valuation, and memory management. The failure to prevent the overgeneralization of fear responses likely relates to an increased risk for both depression and anxiety.

Furthermore, greater general distress over 30 months was associated with less discrimination in the brain during fear extinction recall. The practical implication of this finding may be that when we are less able to look back and tell apart safe from unsafe conditions. When our memories continue to be filled with threat and unable to help us know we are in the clear, the risk of anxiety and depression is higher via overall increased strain and retrospective confusion between threat and non-threat.

In this study, the subgenual anterior cingulate cortex (sgACC) – an area of the brain involved with emotion regulation – was associated with difficulty with accurate fear extinction recall.

Implications for Clinical Care

This study has important implications for our understanding of what anxiety, depression, and other psychiatric conditions really are, on a biological level, as well as how it plays out in our lives. Understanding the levers of how fear conditioning and extinction of fear-based responses as well as how we interpret and remember distressing event tells us a lot about both how anxiety, depression, and stress-related disorders develop and suggests avenues for clinical intervention.

Understanding the role of fear circuitry allows for better design of medications and interventional treatments, including transcranial magnetic stimulation and novel therapeutics including ketamine and intranasal esketamine, psychedelics like MDMA, and psilocybin, and other emerging treatments.

Interestingly, restoring connectivity with the sgACC and the dorsomedial prefrontal cortex (dmPFC) is a marker of a good antidepressant response to transcranial magnetic stimulation (TMS) for treatment-refractory depression (2019).

The recent Stanford SAINT TMS protocol, which uses the turbocharged theta-burst pattern of magnetic stimulation of the dmPFC to target the area most strongly connected with the sgACC, with nearly an 80 percent remission rate in early studies (2021).

Psychotherapy can help people struggling with a variety of symptoms to focus on properly differentiating threat from safety, for example, improving fear extinction and helping to shape healthier and more constructive narratives about past events as well as learning to tell the better judge upcoming threats from situations which may be safer, but perceived as threatening – especially important in personal and professional settings, and in solitude, in our relationship with ourselves.

This is true both looking back and reworking past experiences, a process Freud called "nachträglichkeit" (or "afterwardness"), as well as in making sense of new experiences.

To find a therapist, visit the Psychology Today Therapy Directory.



1. ROIs included the amygdala, hippocampus, anterior insula, dorsal ACC, subgenual ACC, vmPFC and bed nucleus of the stria terminalis, all involved in emotion regulation, self-awareness and memory, contextualization of fear-based reactions, discrimination of brain signals and decision-making/valuation, and development of habitual responses.

Yujia Peng, Jeffrey D. Knotts, Katherine S. Young, Susan Y. Bookheimer, Robin Nusslock, Richard E. Zinbarg, Nicholas J. Kelley, Aileen M. Echiverri-Cohen, Michelle G. Craske, Threat Neurocircuitry Predicts the Development of Anxiety and Depression Symptoms in a Longitudinal Study, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging,
2022, ISSN 2451-9022,

Ruiyang Ge, Jonathan Downar, Daniel M. Blumberger, Zafiris J. Daskalakis, Fidel Vila-Rodriguez, Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up, Brain Stimulation, Volume 13, Issue 1, 2020, Pages 206-214, ISSN 1935-861X,

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial, Eleanor J. Cole, Angela L. Phillips, Brandon S. Bentzley, Katy H. Stimpson, Romina Nejad, Fahim Barmak, Clive Veerapal, Naushaba Khan, Kirsten Cherian, Emily Felber, Randi Brown, Elizabeth Choi, Sinead King, Heather Pankow, James H. Bishop, Azeezat Azeez, John Coetzee, Rachel Rapier, Nicole Odenwald, David Carreon, Jessica Hawkins, Maureen Chang, Jennifer Keller, Kristin Raj, Charles DeBattista, Booil Jo, Flint M. Espil, Alan F. Schatzberg, Keith D. Sudheimer, and Nolan R. Williams, American Journal of Psychiatry,

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