Key Takeaways
1. Anxiety is a distinct state, not merely extreme fear.
We suggest that risk assessment is the central component of an anxiety pattern, while the reactions to present threat are best characterized as indicating fear.
Ethological distinction. Our understanding of anxiety begins with a fundamental ethological distinction between reactions to actual, present threat (fear) and potential, uncertain threat (anxiety). Fear elicits immediate fight, flight, or freezing responses, aimed at escaping danger. Anxiety, conversely, arises when an animal must approach a potentially dangerous situation, leading to behavioral inhibition and risk assessment.
Functional requirements. These two states have distinct functional requirements and behavioral outputs.
- Fear (Fight-Flight-Freeze System - FFFS): Active escape, defensive aggression, freezing. Triggered by immediate, localized danger (e.g., a predator).
- Anxiety (Behavioral Inhibition System - BIS): Behavioral inhibition (of prepotent responses), increased vigilance, risk assessment behaviors (e.g., stretched-attend posture). Triggered by potential, diffuse danger, especially when approach is also required (approach-avoidance conflict).
Clinical relevance. This distinction is crucial for clinical understanding. Simple phobias, for instance, are seen as fear-based (active avoidance of a specific object) and are often insensitive to anxiolytic drugs. Generalized anxiety, however, involves the uncertainty and conflict characteristic of anxiety, making it responsive to these medications.
2. Anxiolytic drugs are a precise probe for anxiety's neural mechanisms.
Neural or behavioural effects shared by both classical and novel anxiolytic drugs have, therefore, a high probability of delineating processes involved in clinical anxiety or in its amelioration.
Common actions. The diverse chemical structures and primary pharmacological actions of classical (e.g., benzodiazepines, barbiturates) and novel (e.g., buspirone, imipramine) anxiolytic drugs make their shared clinical efficacy and behavioral effects in animals a powerful tool. This commonality allows us to isolate the core mechanisms of anxiety, filtering out drug-specific side effects.
Behavioral profile. Anxiolytic drugs consistently:
- Reduce passive avoidance.
- Impair extinction of previously rewarded responses.
- Improve two-way active avoidance (by reducing inhibition of returning to a previously shocked area).
- Disrupt performance in complex spatial tasks like the Morris water maze.
- Reduce conditioned suppression and the partial reinforcement extinction effect.
Electrophysiological signatures. Crucially, all clinically effective anxiolytics produce two specific changes in hippocampal theta activity:
- Elevate the threshold for septal driving of hippocampal theta at ~7.7 Hz.
- Reduce the frequency of reticularly elicited theta.
These unique electrophysiological signatures, not shared by non-anxiolytic drugs, strongly link anxiolytic action to septo-hippocampal function.
3. The Septo-Hippocampal System (SHS) is anxiety's core neural substrate.
The heart of the theory—that anxiolytic drugs act on a behavioural inhibition system which overlaps substantially at the neural level with the septo-hippocampal system—seems healthier than ever.
Drug-lesion concordance. A striking parallel exists between the behavioral effects of anxiolytic drugs and those of experimental lesions to the septo-hippocampal system. This concordance, observed across a wide range of tasks, suggests that the SHS is a primary site of anxiolytic action and, by extension, a key mediator of anxiety.
Beyond correlation. This isn't just correlation; direct manipulation confirms causality.
- Reproducing the anxiolytic-induced changes in hippocampal theta control (e.g., via noradrenergic depletion or benzodiazepine injection into the supramammillary nucleus) mimics the behavioral effects of systemic anxiolytics.
- Conversely, experimentally inducing electrophysiological changes opposite to those caused by anxiolytics produces opposite behavioral effects.
Partial overlap. While the SHS is central, it's not the sole mediator of anxiety. The theory acknowledges a "partial overlap" with other systems. For instance, the arousal and autonomic components of anxiety are primarily mediated by the amygdala, which also receives direct anxiolytic action. This integrated view positions the SHS as crucial for the cognitive and inhibitory aspects of anxiety, while the amygdala handles the more visceral components.
4. The SHS functions as a "goal conflict detector."
The hippocampus—an organ of hesitation and doubt.
Core function. The fundamental computational role of the SHS is to detect and resolve conflicts between concurrently activated, incompatible "goals." A "goal" is a combined representation of a desired outcome, encompassing both the stimuli associated with it and the response tendencies it elicits.
Conflict resolution mechanism:
- Detection: When multiple goals are highly and equally activated (e.g., approach food vs. avoid predator), the SHS detects this conflict.
- Negative Bias: It resolves conflict by recursively increasing the valence of affectively negative information associated with the competing goals. This biases the system towards avoiding negative outcomes.
- Inhibition & Exploration: This process inhibits prepotent, potentially incorrect behaviors and, if information is insufficient, triggers information-gathering (risk assessment) behaviors.
Beyond simple comparison. This is more sophisticated than a simple stimulus-response comparator. The SHS doesn't just detect mismatch; it actively intervenes to re-evaluate and re-prioritize goals based on their potential negative consequences, ensuring adaptive behavioral selection. This explains why SHS lesions lead to persistent, maladaptive behaviors in conflict situations.
5. Amnesia is "catastrophic hypermnesia," not memory loss.
In our view, ‘amnesia’ resulting from hippocampal damage could more properly be described as ‘catastrophic hypermnesia’, exemplified by reports of apparent failure to retrieve correct items because of intrusion errors (i.e. retrieval of items that were previously correct but are now incorrect).
Reinterpreting memory deficits. The traditional view of amnesia as a failure to form or retrieve memories is challenged. Instead, hippocampal damage leads to a failure to suppress inappropriate or interfering memories. The memory itself is often intact, but it's overwhelmed by a "pandemonium" of competing information.
Interference is key. Tasks sensitive to hippocampal damage are those with high levels of interference, where multiple, often previously correct, responses compete.
- Amnesics often make "intrusion errors," recalling items that were correct in previous trials but are currently incorrect.
- Cued recall, which reduces the number of competing alternatives, significantly improves amnesic performance.
- Hippocampal lesions do not increase the rate of forgetting, but rather reduce the initial discriminability between correct and incorrect items.
No memory storage. The SHS is not a temporary or long-term memory store. Its role is to modulate memory formation and retrieval in other cortical areas by filtering out irrelevant or conflicting associations, ensuring that only the most adaptive information guides behavior. This "anti-processing" function prevents the brain from being flooded with a superfluity of incorrect memories.
6. Hippocampal "place fields" represent "available goals," not just spatial location.
The discharge correlates for location and for task-related behaviours appear to be extremes of a continuum of responses in a single population of neurones.
Beyond spatial maps. While hippocampal neurons exhibit "place fields" (firing when an animal is in a specific location), this is not their exclusive or primary function. A deeper analysis reveals that these fields are flexible and context-dependent, reflecting more than just allocentric spatial position.
"Available goals" hypothesis: Hippocampal cells fire in relation to "available goals" within an environment, which often have spatial components.
- Fields can shift or disappear if the motivational significance of a location changes.
- The same cell can have different fields in different environments or tasks (spatial vs. non-spatial).
- Fields are influenced by task demands and the animal's behavioral context (e.g., directionality depends on stereotyped trajectories).
Path integration. The SHS is crucial for "path integration" – maintaining a sense of location through self-motion cues. This is seen as a specialized form of sequencing successive goals to achieve an objective. The "placeness" of fields arises because goals are frequently tied to specific locations.
Topographic mapping. The SHS likely contains a topographic map of "goal space," where different regions process different types of goal-related information (e.g., "what" vs. "where" aspects of goals along the septo-temporal axis). This organization allows the SHS to target specific goal-processing systems for conflict resolution.
7. Anxiety involves recursive SHS-Amygdala interactions.
In particular, in the present edition, we see anxiety as resulting, in its most fundamental form, from interaction between the septo-hippocampal system and the amygdala.
Integrated emotional response. Anxiety is not solely mediated by the SHS or the amygdala, but arises from their dynamic, recursive interaction.
- SHS role: Detects and resolves goal conflict, increasing negative cognitive bias.
- Amygdala role: Coordinates arousal and autonomic outputs (e.g., fear-potentiated startle, heart rate changes), providing the "gut feeling" of anxiety.
Mutual influence. The SHS influences the amygdala by amplifying negative affective bias, thereby increasing passive avoidance tendencies. Conversely, the amygdala provides the SHS with specific threat information, especially when fear is a component of the conflict. This short, recursive loop is crucial for generating the full spectrum of anxiety symptoms.
Beyond simple summation. This interaction is not a simple sum of individual functions. The recursive nature allows for complex, escalating feedback loops. For example, SHS-mediated worry can intensify amygdala-driven arousal, which in turn feeds back to heighten perceived threat, creating a vicious cycle characteristic of pathological anxiety.
8. Anxiety disorders stem from specific defence system dysfunctions.
A particular symptom (e.g. panic or obsession) is deemed to result from a high level of activity in the relevant site indicated in the diagram.
Hierarchical defence. The brain's defence system is hierarchically organized, with different structures mediating distinct responses to threat based on defensive distance and direction.
- Periaqueductal Grey (PAG): Undirected escape, defensive aggression, freezing (panic).
- Medial Hypothalamus (MH): Directed escape.
- Amygdala (AMYG): Simple active avoidance, fear conditioning (phobia), arousal.
- Septo-Hippocampal System (SHS): Passive avoidance, risk assessment, conflict resolution (anxiety).
- Anterior Cingulate Cortex (ACC): Complex active avoidance, innate rituals (obsessions/compulsions).
- Prefrontal Cortex (PFC): Higher-order planning, linguistic control over anxiety.
Symptom vs. Syndrome. A symptom (e.g., panic attack) can arise from primary dysfunction in its dedicated neural center (e.g., PAG in panic disorder) or secondarily from excessive activity in other interconnected regions (e.g., extreme anxiety triggering panic). This explains comorbidity and the complex presentation of disorders.
Pharmacological distinctions. Different drug classes target specific components:
- Anxiolytics: Primarily SHS, secondarily AMYG (reduce anxiety).
- Anti-panic drugs: Primarily PAG (reduce panic).
- Clomipramine: Primarily ACC/basal ganglia (reduce obsessions/compulsions).
This differential sensitivity underscores the distinct neural underpinnings of these anxiety-related conditions.
9. Neuroticism is a heritable, unified predisposition to anxiety.
The overall pattern of differences between the Maudsley strains is, thus, consistent with the hypothesis that they differ in sensitivity to the overall effects of threatening stimuli.
Dimensionality of personality. Anxiety-related disorders are not discrete illnesses but extreme points on continuous personality dimensions, particularly Neuroticism. Individuals high in Neuroticism are generally more susceptible to threat.
Genetic basis. Neuroticism is substantially heritable (~50%), suggesting polygenic influence. Quantitative Trait Locus (QTL) analysis in rodents (e.g., Maudsley rats, DeFries mice) identifies chromosomal regions linked to "emotionality" traits like open-field defecation and activity.
- A single pleiotropic QTL on mouse chromosome 1 affects both anxiolytic-sensitive (elevated plus maze) and anxiolytic-insensitive (open-field defecation) behaviors.
- This indicates that genes influence operating characteristics of both the BIS and FFFS.
Unified susceptibility. What is inherited is a broad propensity to react to threatening stimuli, affecting a wide array of emotional behaviors and predisposing individuals to various neurotic disorders (panic, phobia, anxiety, depression). This genetic influence likely shapes fundamental parameters of the distributed defence system, such as overall threat detection sensitivity or the functioning of modulatory monoaminergic pathways.
10. Cognitive-Behavioral Therapy (CBT) targets maladaptive threat appraisal.
The cognitive model of panic disorder states that: Individuals who experience recurrent panic attacks do so because they have a relatively enduring tendency to interpret certain bodily sensations in a catastrophic fashion.
Cognitive distortions. CBT is founded on the principle that maladaptive cognitive appraisals (erroneous beliefs, dysfunctional information processing) drive pathological emotions and behaviors. Therapy aims to identify and alter these distortions.
Mechanism of action:
- Panic Disorder: Targets catastrophic misinterpretations of bodily sensations (e.g., palpitations = heart attack). Therapy involves identifying triggers, challenging beliefs, and behavioral experiments (e.g., inducing sensations to disconfirm fears).
- Social Phobia: Addresses negative assumptions about social situations and self-monitoring biases (e.g., "I'm being boring" from a brief glance). Therapy focuses on re-evaluating social interactions and reducing safety behaviors.
Reducing excessive weighting. CBT's core effect is to reduce the excessive weighting of potential adverse outcomes associated with specific stimuli. This aligns with our theory's view of anxiety as involving an increased negative cognitive bias.
Long-term efficacy. Unlike pharmacotherapy, which often only manages symptoms, CBT aims for long-term changes in thought habits, leading to sustained recovery and relapse prevention. Its broad efficacy across diverse anxiety-related disorders suggests it acts on a common, higher-level mechanism of threat appraisal.
11. The SHS modulates threat perception, not just memory.
The septo-hippocampal system, at the neural level, as being of critical importance to a behavioural inhibition system at the psychological level; and we see these systems as giving rise to pathological anxiety when hyperactive, and to amnesia when hypoactive.
Unified function. The SHS's role extends beyond memory to a fundamental modulation of threat perception and behavioral control. Its core function is to resolve goal conflicts by increasing negative affective bias, which impacts both memory (by suppressing incorrect associations) and emotional states (by heightening perceived threat).
Bidirectional pathology.
- Hyperactivity (Anxiety): Excessive SHS output leads to increased negative bias, heightened risk assessment, and pathological anxiety (e.g., generalized anxiety disorder). This aligns with cognitive theories emphasizing distorted threat appraisal.
- Hypoactivity (Amnesia): Impaired SHS function leads to a failure to suppress competing, incorrect information, resulting in "catastrophic hypermnesia" and memory deficits.
Cognitive-emotional link. The SHS acts as a crucial interface between cognitive processing (e.g., evaluating potential outcomes, managing interference) and emotional responses (e.g., generating anxiety, influencing amygdala-mediated arousal). This integration is vital for adaptive behavior in complex, uncertain environments.
Therapeutic implications. Understanding the SHS's role in biasing threat perception provides a framework for both pharmacological and psychological interventions. Anxiolytics dampen this bias, while CBT aims to re-educate the system to appraise threats more realistically, ultimately influencing the SHS's output and its interactions with other defence systems.
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