Behavioural observation of patients with anxiety disorders suggests that these disor-
ders–as a group–reflect exaggerated responses to
internal or external signals
of perceived danger or
threat.
The autonomic part of the anxious response pattern prepares the organism
for one of several behavioural options to terminate the anxiety-eliciting situation,
namely flight,immobility, submission, or aggression.
In gregarious species like primates and humans, some fear reactions may have an altruistic
connotation in that a fear reaction of one individual may alarm others about impending
danger.
Alarm calls are found in many primate species and can be truly seen as altruistic
behaviour because the call is clearly at the cost of the alarming individual, which runs the
risk of attracting the attention of predators, and because the alarming individual has no
immediate pay-off from warning its conspecifics.
In any event,fear(the term referring best to the 'normal' adaptive variant) and anxiety
(reflecting pathologically exaggerated fear in terms of duration,intensity
or situational appropriateness) clearly belong to a
group of defence mechanisms, much like submission and depression do.In contrast to
depression,it is intrinsic to the anxiety disorders that anxiety attacks usually cease
automatically, and often aim more directly at eliciting care from others (like in PD or
agoraphobia). Moreover, situations causing anxiety can better be avoided than those
leading to depression. Whether or not some form of altruistic behaviour is reflected in
anxiety disorders is open to speculation. Arguably, altruism is part of OCD-associated
pathology, where others (usually closely related individuals) may benefit from exagger-
ated hygiene or repetitive control of potentially dangerous situations.
Phobic fears of specific situations, objects or persons are so widespread that they
inevitable constitute a significant part of human nature, much of which is inherited from
our primate ancestors. For example, during normal human ontogeny, separation from
the primary caregiver, heights, or strangers are among the strongest fear-evoking situa-
tions,to which the human infant is biologically prepared to respond. Not only are these
fear responses particularly prevalent durin
g certain developmental periods; separation
distress occurs soon after birth,fear of heights emerges when the infant starts to crawl,
fear of strangers when the toddler begins to give up physical closeness to the mother for
brief periods of time, and so forth. These fear reactions are operate on actual sources of
fear that were persistent enough in the environment of evolutionary adaptedness (EEA)
to be selected. Their way of functioning has been likened to the principle of a 'smoke
detector' mechanism, which works optimally if the threshold is low enough to reliably
produce a response to potentially life-threatening Stimuli at the cost of some raise alarms,
but high enough to limit the costliness of too many energetically
expensive false alarms. Here,it needs to be emphasized that not responding to a genuine threat
(for instance, in a predation situation)is most expensive, because
it may cause death of the individual;thus, behaviour too dauntless would readily be
eliminated by natural selection, and a lack of fearfulness would not translate into greater
reproductive fitness.
In primates including humans, phobic fear reactions are not only acquired through
direct conditioning experiences, but also through vicarious experiences,in which an
individual witnesses the response of another individual to fear-relevant stimuli. These
are probably the most important mechanisms of how biologically predisposed fears
become actually manifest. For example,fear of snakes is most likely not 'innate' in
primates, but requires observation of fear responses of conspecifics to the sight of a
snake. However, although conditioning seems to be necessary, biological preparedness is
also likely involved, because no such reactions can be experimentally conditioned when
using flowers instead of snakes as conditioned stimuli. Even though these conditioning
models may be more valid for between-species fears than same-species (social) phobic
fears,it is most obvious that normal fear-conditioning and pathological phobia and
other anxiety disorders lie along a continuum. This is true for all psychopathological
signs and symptoms, and anxiety disorders are paradigmatic in this respect.
Normal fear conditioning takes place early in life. For example, a young primate may
easily acquire fear of snakes through attending to its mother's reaction. The extraordinary
importance of physical closeness for young primates and humans supports the assump-
tion that individual differences in attachment exert long-lasting effects on how young infants and children learn to cope with fear-inducing situations.If,for instance,the
primary caregiver is unresponsive to the infant's needs
or even unavailable,insecure
attachment is likely to develop. Consequently,
ambivalently or avoidantly attached infants are
more vulnerable to develop anxiety disorders later
in life. In line wlth this, patients with various forms
of anxiety disorders have experienced early losses
more often than controls,report rejection by parents
more frequently, or have experienced extremely
inadequate caregiving more often compared
to controls. This makes sense in light of the hypothesis that insecurely attached
individuals are prepared through adverse early experiences to develop mistrustful inner
working models and to see the world as a hazardous place.
Gene-environment interactions leading to anxiety disorders seem to predispose these
individuals to assume behavioural strategies aiming at harm avoidance and acquiring
defence strategies associated with internalizing symptoms (which explains the frequent
comorbidity of anxiety disorders with depression).In line with this assumption, carriers
of the short polymorphic version of the serotonin transporter gene have been found
to develop depression or anxiety disorder after negative life events more often than
individuals who lack this allele variant.
Early experiences may,therefore, 'shape' the responsivity of neurobiological circuits
involved in fear responses. For example, evidence from brain imaging studies suggests
exaggerated sensitivity of the amygdalae to fearful stimuli in patients with PTSD or SAD.
In addition,the reduced control over fear responses may be augmented by a diminished
emotional evaluation of threat signals (projected from the amygdala to prefrontal cortex
areas), and insufficient integration of representation of past experiences (via the
hippocampal formation).In other words,in sensi-
tized individuals,irrespective of whether sensitiza-
tion is genetically predisposed, acquired through
aversive experience or both,the amygdala may lose
the inhibitory control through which it normally contains the approach of novel objects I
or other organisms (including individuals of the same species).Instead the amygdala,
responds in a dysregulated or hyperactive fashion such that benign environmental
stimuli may be perceived dangerous. All this may result in exaggerated avoidance behav-
iour and subjectively overwhelming feelings of intense fear in vulnerable individuals.
Conceivably, humans may be particularly susceptible to dysregulation of fear
circuits
for several reasons, which may account for the high prevalence rates of anxiety disorders.
Firstly, since humans are exceptionally social, but physically vulnerable,they may be
inclined to constantly check their environment for potential sources of threat(both from
outside and from within the social group). This may not only include predatory or phys-
ical threat, but also threat of social status and loss of resources.In support of this
assumption,the neuroanatomical structures involved in the evaluation of potentially
dangerous situations have increased in size over evolutionary time, WⅡich underscores
theirimportance in terms of survival and reproductive success. Secondly, newborn
humans critically depend on intense nurturance and care, such that a stable affectional
bond with a primary caregiver is outstandingly vital for survival.If, however, stability of
an affectional bond is unattainable or disrupted (for example, by loss of the primary
caregiver), a hypersensitive and constantly overaroused fear system may result. Such a
situation may dramatically worsen,if physical or
emotional abuse is involved with which an imma-
ture human infant can hardly cope. Thirdly, humans
have evolved the capacity to anticipate future
scinario, which on one hand, was certainly highly
adaptive with regards to foreseeing food shortages
or other potentially perilous situations including
changing alliances between contenders ; on the other
hand, exaggerated anticipation of threat and danger
seems to be immanent to various forms of anxiety
disorders , which may ,in part , explain why patients often report fear of recurrence of
anxiety (anticipatory anxiety). Finally,it could be that in modern societies the dimin-
ished necessity to cope with fear-inducing situations–simply due to a reduced number
of dangerous encounters with poisonous animals or predators–renders the neurobio-
logical system involved in evaluation of potential hazards more labile and 'unprepared' to
accurately respond to real-life confrontation with spiders, snakes or heights. However, a
notable exception could be potential or actual harm caused by conspecifics.In modern
societies,individuals frequently meet other people, whom they have seen never before,
and whose intentions are much harder to determine than in familiar people. This may
cause particular problems for those individuals who have developed mistrustful inner
working models and are cognitively biased towards assuming malicious intents in others.
In fact, patients with anxiety disorders frequently complain that others can virtually see
what is wrong with them, and feel being observed or stared at(in contrast to delusional
beliefs, patients with anxiety disorders do not report in corrigible conviction that this is
true; continua between extreme anxiety and paranoid ideation may, however, exist).
Although the preceding paragraphs have dealt with anxiety disorders as if they were
different manifestations of a singular diathesis,they differ,to some extent,in neurobiol-
ogy and precipitating events.
PD is perhaps the most primitive of the anxiety disorders. For example, PD has been
interpreted as false suffocation alarm, because carbon dioxide inhalation or lactate
infusion may produce panic attacks in vulnerable
(healthy)individuals. Moreover, PD occurs more
frequently in individuals with heightened PCO2 levels, e.g. during sleep, during the
premenstrual period and in patients with respiratory disorders. On the other hand, PD is
less common in physiological states associated with lowered PCO;,including pregnancy
and delivery. Although there is some evidence that the genetic vulnerability is most prominent in PD compared to other anxiety disorders, additional environmental factors
such as loss of an attachment figure may be equally important in that such events may
lower the suffocation alarm threshold. Panic attacks may therefore be seen as the extreme
version of a preparatory set of physiological changes typical of immediate flight or
escape behaviours. Anticipatory anxiety is often the result of recurrent panic attacks.
Thus, at the cognitive level PD involves the mental representation of future negative
events.In neurobiological perspective, PD probably involves hyperexcitability of norepi-
nephrine pathways and reduced serotonergic and GABA-ergic dampening of limbic
structures.In light of the putative association of PD with separation distress, a link with
abnormal oxytocin turnover is conceivable.
Agoraphobia, which often accompanies PD,reflects an exaggerated response to avoid
(claustrophobia). Agoraphobia,like PD,IS probably
the pathological extreme of an evolutionarily
conserved behavioural pattern that is common to many animal species and helps to
protect the organism from entering unknown terrain that could yield a predatory threat
or hostile attacks from conspecifics. Whether or not agoraphobia differs from PD in
neurobiology or simply represents a more severe and complex form of PD is debatable.
Shared genetic vulnerability between agoraphobia and PD and associations with similar
precipitating life events may support the latter assumption.< /span>
SAD is characterized by intense fear of social situations in the presence of an authorita-
tive person. Social phobia can be interpreted as an exaggerated submissive gesture
triggered by situations that may potentially lead to humiliation and loss of social status.
There are some phenomenological parallels
lap with normal blushing, which,in extreme forms,
develop into erythrophobia,the fear of reddening
of the skin as a visible signal of the subjective
state of embarrassment. SAD causes a dilemma, especially in its generalized form, because
fear and anxiety usually elicit care and comforting behaviour in others, which the affected
individual cannot tolerate In fact, heightened attention from others may even aggravate
the phobic reaction. The difference to other anxiety disorders is that in SAD patients tend
to exaggerate the evaluation of mental states of others. Unlike patients with autism or
schizophrenia who have difficulties in representing mental states of others (reduced
mentalizing in the former,inaccurate hyper-mentalizing in the latter), patients with social
phobia are well able to appropriately reason about other persons' mental life;in specific
situations, which are perceived as posing a threat to social status and reputation, however,
they negatively interpret social signals of others and may over-anticipate a personally
appalling outcome of social encounters. Research in animals and humans strongly suggest
a central role of amygdala dysfunction in SAD. This dysfunction may be mediated by
reduced availability of GABA and serotonin as well as by impaired regulation of affiliative
behaviour and social attachment via oxytocin. Moreover,reduced inhibition of amygdalar
function through glutamatergic prefrontal efferents (via GABA-ergic interneurons) has
been identified as potential proximate causation of SAD.
GAD is,in contrast to phobic anxiety, not explicitly associated with particular precipi-
tating events. GAD rather reflects an overall tendency towards hypervigilance, probably
forming a continuum with avoidant personality
disorder.It is the least heritable anxiety disorder
and therefore depends even more than the other
anxiety disorders on early aversive subjective experiences and learned behaviour. Chronic
hyper-excitability,restlessness and increased muscle tension is likely to involve the HPA
axis, which may induce secondary physical problems including chronic arterial hyperten-
sion and other stress-related disorders.
Within the broa
der spectrum of anxiety disorders, OCD stands out by its marked
repetitive and stereotyped behavioural subroutines. From an ethological perspective,
OCD-associated behaviours resemble displacement activities (compare Chapter 5) and
stereotyped behaviours observed in animals under physical restraint.In OCD, however,
the repetitively displayed behaviours clearly address harm-avoidance by checking,
washing, ordering or hoarding.Interestingly, OCD manifests or worsens in biologically
relevant situations such as pregnancy and following childbirth. OCD-associated behav-
iours are thus abnormal by their excessiveness, but probably qualitatively not distinct
from adaptive harm avoidance strategies. Even though anticipation plays an important
role in many anxiety disorders,the cognitive mechanism of mentally generating future
scenarios that may cause harm to self or others is decisively at the core of OCD. Humans,
unlike most other animals, have evolved the capacity to cognitively represent imagina-
tions of past and future events by using semantically and autobiographically stored
memories. This is certainly selectively advantageous, because future threats or needs can
be dealt with in advance (e.g. by collecting food without being hungry). The difference to
hibernating animals is that the cognitive represen-
tation of possible future scenarios is not instinct-
driven (hibernators collect food even if they have
never experiences winter time before), yet much more flexible.In other words,this kind
of cognitive representation is independent of situation and content,i.e. one can create
social or non-social future events as mental images.In the case of OCD,it would seem
that it is exactly this mechanism that is over-active and–despite insight into the
bizarreness of obsessive thoughts and compulsive behaviours–difficult to control.
At the neurophysiological level, OCD not only involves abnormal serotonergic activity,
but also increased dopaminergic transmission, which may cause an imbalance of phylo-
genetic older 'habitual' systems and phylogenetic younger 'flexibility' systems. Flexible
responses involve the capacity of selecting the relevant sensory input, shifting the atten-
tional focus, making the best choice of behavioral alternatives, and sometimes suppress-
ing salient responses in favour of less salient ones.In primates and humans,the
dorsolateral prefrontal cortex,the orbitofrontal cortex,the cingulate cortex,the supple-
mentary motor cortex, pallidostriatal structures, and parts ofthe thalamus contribute to
the execution of flexible behaviour, where striatum and thalamus operate as filter of
incoming information and project back to different areas of the frontal cortex. These
brain regions have been found hyperactive in OCD. Moreover, enhanced brain activity in the anterior cingulate cortex,in the prefrontal cortex,the dorsolateral prefrontal cortex,
and dorsal prefrontal cortex has been shown to be associated with episodic memory
retrieval in healthy individuals,'prospective memory,that is,the ability to keep in mind
something that needs to be carried out in the future, and,in part, with anticipatory anxi-
ety These findings underscore the assumption of a significant role of exaggerated cogni-
tive risk anticipation in OCD.
Similar mechanisms may also contribute to PTSD, however, with the difference that the
manifestation of PTSD is, by definition , proceed by
a severe traumatic event—in OCD,real danger ma
have never been encountered. Furthermore,in
PTSD,re-experiencing a traumatic event that lies in the pastis at the core of the sympto-
matology, and much less so the mental imagination of future (novel)traumatizing scenar-
ios. Remembering past situations associated with threat or actual harm is certainly
adaptive in that it helps to avoid similar future negative experiences;in PTSD, however,
this mechanism is pathologically hyperactive to the extent that it may actually preclude
adaptive responses, but instead gives why to phylogenetically primitive fear reactions such
as 'freezing' and dissociative states (regarding catatonic/dissociative behaviours, compare
Chapter10). Similarto OCD, however,in PTSD intrusive thoughts and memories are
perceived as uncontrollable, and usually generate strong autonomic arousal, chronically
heightened vigilance, and persistentfeelings ofimpending danger.It would seem that
individuals with PTSD are unable to disentangle past, present, and future threat scenarios
in that they re-experience in the present what frightened them in the past. Hence, at the
physiological level, PTSD represents a hyperactivity of the alarm system associated with
chronic up-regulation of the HPA axis, which,in turn,impairs integration of traumatic
experiences and appropriate memory consolidation. Moreover, even though the amygdala
is hyperactivated during recollection of traumatic events, normal threat evaluation is
impaired such that the affected individual is less well able to distinguish between relevant
and irrelevant stimuli as potential sources of danger.In addition,the communication
between right('emotional') and left('rational') hemisphere seems to be functionally
disrupted in PTSD, such that traumatic memories may be experienced as ego-alien,
because the emotional aspects of the traumatic experience cannot be appropriately
verbalized.It is plausible to assume that the changes at the physiological and
neuroanatomical level in PTSD are the more severe the earlier the individualis confronted
with a traumatic experience. Early childhood trauma,for instance, may induce pervasive
alterations of neural circuits underlying emotion processing and emotion regulation.In
light of the lateralization of the functions, severe early traumatization may affect more
strongly the right rather than the left brain.
In summary, anxiety disorders represent pathologically exaggerated defence mecha-
nisms, which primarily manifest at the emotional, but also at the corresponding and
interconnected behavioural and cognitive level. Anxiety disorders differ to some extent in
their genetic underpinnings and environmental causation. All anxiety disorders have in
common, however,that they can be triggered by social experiences and are influenced by
different modalities of associative (social)learning. Unlearning the conditioned response
is sometimes hard to manage , such that preventive measures including prevention
of early traumatization and strengthening of resilience are crucial aspects of any
therapeutic effort.