Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Functional Neuroanatomy of Anxiety Disorders

Brian Martis, Andrea Malizia and Scott L. Rauch


In this chapter, current hypotheses regarding the functional neuroanatomy of anxiety disorders are examined. Initially, the concepts of anxiety and stress as well as anxiety disorders are discussed. Next, relevant research on animal fear conditioning as well as human anxiety studies are briefly reviewed. This provides the necessary foundation for the ensuing coverage of human data on anxiety disorders and related contemporary neurobiological models.

Anxiety and Fear

In humans, anxiety is a normal unpleasant affective state with experiential, cognitive, autonomic, neuroendocrine and behavioural components. Fear behaviour is the response to specific environmental stimuli that are perceived as potentially dangerous. Though details are still debated, fear behaviour refers to a stimulus-bound response while anxiety is understood as a state of anticipatory apprehension and dread in humans (Davis, 1998; Nitschke, Heller and Miller, 2000). Fear processes are innate and mediated by rapidresponse neurobiological systems in animals and humans. It is appealing to consider that these adaptive mechanisms have evolved to enable harm avoidance and enhance chances of survival. Animal research findings suggest that the fear system is a dynamic, integrated network of neural circuits, comprised of processing nodes (specific brain areas), that detects and responds to danger (LeDoux, 2000a). Given the wealth of behavioural and neurobiological similarities between fear responses in animals and humans, animal research in this area plays an important role in guiding anxiety research in humans. However, the conscious and cognitive aspects of human anxiety are undeniably complex and unique, thereby warranting caution when extrapolating from fear research in animals to the neurobiology of anxiety in humans. Similarly, there are substantial inferential leaps to be acknowledged when moving from theories regarding normal human anxiety to the anxiety disorders, which are complex, multifactorially determined syndromes.


Stress is generally defined as a circumstance that disturbs the normal physiological or psychological functioning of an individual, as well as the disturbed state that results (derived from The Oxford English Dictionary, Second Edition, 1989). Physiological stress responses are coordinated, multisystem (e.g. autonomic, neuroendocrine and immune) adaptive changes in organisms. Stress inducing stimuli or 'stressors' can be positive or adverse. Stress research in humans is particularly challenging due to the convergent and less well described effects of psychological, social and cultural stressors on biological systems. Excessive stress in humans contributes to increased morbidity and mortality and is a significant predictor of adverse outcomes in many medical and psychiatric disorders, e.g. ischaemic heart disease and major depression (Chrousos and Gold, 1998; O'Connor, Gurbel and Serebrauny, 2000; Monroe et al., 2001). Stress responses are closely related to anxiety disorders; this being inferred mainly from overt exposure to stressful life events or trauma. The effects of chronic low level stress are less well established in relation to psychiatric disorders. In the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; APA, 1994), two disorders, Acute Stress Disorder and Post-Traumatic Stress Disorder, specifically require exposure to overt traumatic stress as a diagnostic criterion.

Anxiety Disorders

Anxiety disorders, (DSM-IV, (APA, 1994); ICD 10, under 'neurotic, stress-related and somatoform disorders', Chapter V (F), WHO, 1992), are characterized by exaggerated anxiety and fear responses occurring either spontaneously or to relatively innocuous stimuli. Additional hallmarks of these disorders include hypervigilance, hyperarousal, ritualized avoidance and subjective distress. When severe, these manifestations can be disabling. Sufferers tend to display attention and interpretation biases resulting in hypervigilance and overestimation of risk (Nitschke, Heller and Miller, 2000). Psychiatric comorbidity is common among individuals who suffer from an anxiety disorder; the most prevalent comorbid conditions include another anxiety disorder, depression, and substance use disorders. People with anxiety disorders are also at increased risk of suicide and exhibit increased medical service utilization (Regier et al, 1998; Dunner, 2001). Discrete anxiety disorder diagnoses in the DSM-IV include: panic disorder (with and without agoraphobia), acute stress and post traumatic stress disorder, specific and social phobias (social anxiety disorder), generalized anxiety disorder and obsessive compulsive disorder (APA, 1994). Emerging neurobiological evidence provides an opportunity to critically review and refine these nosological constructs, though making sense of inconsistent evidence from studies that involve different modalities and paradigms in heterogeneous populations is a challenge.


Fear Conditioning: Animal Research

The fear-conditioning behavioural paradigm has been a centrepiece for advancing science in this domain via hypothesis-driven research in both animals and humans. Fear conditioning involves the temporal pairing of a neutral stimulus (known as a conditioned stimulus (CS); e.g. a tone), with an aversive stimulus (the unconditioned stimulus (US); e.g. a shock) that can innately elicit fear responses.


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