PSYCHOLOGY Psychology & Neuroscience, 2011, 4, 2, 173 - 181

DOI: 10.3922/j.psns.2011.2.002
NEUROSCIENCE

Fear, anxiety and their disorders: past, present and future

neural theories
Neil McNaughton
University of Otago, Dunedin, New Zealand

Abstract
This paper reviews the historical development of a two-dimensional (direction x distance (?)) neural model of defense.
It begins with Miller’s (1944) analysis, and model, of approach, avoidance and conflict; adds Hinde’s (1966) ethological
perspective and Flynn’s (1967) neural model of fear; and then considers Gray’s (1967, 1970) work linking barbiturate action
to the hippocampus, McNaughton’s (1977) extension of this to other classes of anxiolytics, and Gray & McNaughton’s (1983)
detailed behavioral comparison of anxiolytics and hippocampal lesions. This work led to Gray’s (1982) detailed model of
the neuropsychology of anxiety. Rapoport’s (1989) model of the control of obsession by the cingulate cortex, and Ledoux’s
(1994) model of the control of both fear and anxiety to the amygdala, suggested a more complex organisation of defense
systems. McNaughton (1989) argued that evolutionary function defines an emotion, and Blanchard and Blanchard (1990)
argued for its assessment via ethoexperimental analysis. Graeff (1994) then produced a neural model that mapped defensive
distance to neural level, treating all anxiety as being at a greater defensive distance than fear. Seeing this, and the treatment
of anxiety as due to uncertainty (which is inconsistent with Miller’s data), as being unsatisfactory, Gray and McNaughton
(2000) and then McNaughton and Corr (2004) developed the two-dimensional model of defensive systems. This model is
clearly incomplete at the present time and its links with neuroeconomics, personality, and stress and greater specification of
frontal cortical contributions are suggested as directions for future development. Keywords: fear, anxiety, periaqueductal
gray, hypothalamus, hippocampus, amygdala, cingulate cortex, frontal cortex

Received 4 February 2011; received in revised form 13 March 2011; accepted 17 March 2011. Available on line 10 October 2011

This paper describes the development of the two- controlling movement in one direction or the other. Neal
dimensional neural model of fear and anxiety (McNaughton Miller (who shaped a number of Jeffrey Gray’s early
& Corr, 2004). The ordering of topics in the paper is both ideas) carried out a number of experiments on conflict
close to the order in which I met them academically and leading to a two (approach/avoidance) system model. The
the order of their occurrence historically – but I have made key was to pit approach against avoidance by presenting
some departures from strict temporal sequence to make the both shock and food to a hungry rat in a straight alley.
development of parallel thought streams more coherent and A range of experiments showed that distinct systems
to promote understanding of the content of the later theories. controlled approach and avoidance with, importantly, the
“History” implies retrospection. But what I am telling strength of avoidance decreasing at a greater rate from the
is the story of how I and a field moved forward and, I look goal than that of approach (Figure 1).
into the future because I can see the theory with which
I finish being, for some current postgraduate student, the
equivalent of Miller’s theory of conflict, which started my
own academic journey.

Miller 1944: Conflict - The behaviorist perspective

Approach and avoidance can seem to be opposite

poles of a single dimension, requiring only a single system
Neil McNaughton, Dept. Psychology and Brain Health
Research Centre, Department of Psychology, University of Otago, Figure 1. Miller’s (1944) graphic summary of data on
Dunedin, New Zealand. Correspondence regarding this article approach-avoidance conflict. “The tendency to approach is
should be directed to Neil McNaughton,University of Otago. PO stronger far from the feared goal, while the tendency to avoid
BOX 56, Dunedin, New Zealand. Telephone:+64-3-479-7643. is stronger near the goal” taken with permission from Hinde
Email: nmcn@psy.otago.ac.nz (1966) p. 247. © The McGraw-Hill Companies Inc.
174 McNaughton

Miller model Flynn 1967: A fear system

Miller developed a model (Figure 2) that The early work was not explicit about the neural
explained much about the rate and direction of the systems involved; nor about the way such systems
rat’s movement, including the dithering that tended to could operate. In particular, it was not clear whether an
occur at the cross-over point of the two gradients. This “avoidance system” produced behavioral patterns that the
was a fundamentally behaviorist model – focussing on experimenter could then label as fear-related, or whether
approach and avoidance. But Miller viewed it also as a the system generated a state that could be labelled “fear”,
potentially neurally realistic model. I view him as the which would then generate appropriate behavior.
first in a line of fundamentally neural theorists because,
among other things, he showed that the location of the
conflict point, and the behavior that typically occurs
at it, was sensitive to sodium amylobarbitone (an
anxiolytic commonly prescribed by physicians at the
time). Critically, the drug did not eliminate approach or
avoidance but simply shifted the balance between them,
providing early evidence of a distinct conflict system.

Figure 2. Miller’s model, see text, redrawn from Gray (1971, p.120).

Hinde 1966: Conflict - The ethological perspective Figure 3. Above: Examples of two different forms of attack
produced by stimulation of different systems within the
In parallel with this behaviorist perspective, and hypothalamus. From Flynn (1967), p. 45, with permission. ©
Rockefeller University Press, 1967. Originally published in
linked to it, was analysis by ethologists. Thus, Figure 1 is Neurophysiology and Emotion (D.C. Glass, editor).
a copy in Hinde’s ethological text “Animal Behaviour”
of Miller’s original approach-avoidance analysis – but This issue is addressed by experiments carried out
a key point, for Hinde, of the animal’s behavior was by Flynn (1967) who found that stimulation of slightly
that “...it may run a little way up, hesitate, turn back, different areas in the hypothalamus of a cat could
and oscillate about a point some distance from the goal, cause it to attack a rat with two quite different attitudes
or hesitate there grooming its fur or cleaning its paws” (Figure 3). There was predatory attack involving quiet
(Hinde, 1966, p. 247). That is, conflict is not just a state biting with no sign of fear or other aversive emotion
where approach and avoidance are balanced (which from the cat; and there was a quite different form of
could explain dithering) but it is a state that generates attack (described by Flynn as accompanied by a display
other, relatively unexpected, “displacement” behaviors of rage), indicative of fear.
such as grooming (op. cit. pp. 278-9). This was another Particularly important points about these results
early indication of the operation of an additional system are that, in both cases, if there was no stimulation there
to those of pure approach and pure avoidance – one that was no attack, and also if there was stimulation but no
could generate its own distinctive behavior as well as rat was present, there was no attack (although the rage
altering the balance between the other two. display still occurred). Thus, the stimulation did not
Fear, anxiety and their disorders 175

simply elicit the behavior, it created an internal state Flynn model

that produced a disposition to produce behavior – but
the behavior that was produced was then shaped by Flynn (1967) combined the hypothalamic
environmental stimuli. Not only was a rat required to stimulation data with a large number of other related
release the behavior but the behavior itself was shaped, experiments to produce a neurally explicit model
on a moment by moment basis, by the specific behavior (Figure 5). He distinguished between two types of
being shown by the rat. The stimulation, then, appeared motor output. R1 were essentially “elicited” behaviors
to be eliciting the relevant emotional state. (walking, sniffing, snarling, rage) that were produced
The presumed fear state was elicited from a range by the stimulation in a largely unconditional manner.
of sites within the hypothalamus (Figure 4) suggesting R2 were essentially “released” behaviors, particularly
that these were all part of a distinct hypothalamic fear attack. The latter are controlled jointly by the patterning
system, separate from that controlling predation. This mechanism and external stimulus (S) input via a
led Flynn to an explicit neural model of the release of sensory filter and via a motor disposition. The effects
behavior by the electrical stimulation that shared many of the patterning mechanism are arguably best seen as
elements with the ethological notions of release of reflecting an emotional state that is set up when it is
displacement activities by conflict. activated by the stimulation. Of course, under normal
circumstances this emotional state would be created by
other inputs (e.g., the facilitating mechanism) and also,
in Flynn’s model, could be inhibited.

Figure 5. A model of the fear system to account for the data

of Figures 3 and 4 and a large number of other experiments.
For details, see text. S = external stimuli (the rat); R1 =
“elicited” behaviors; R2 = “released” behaviors. Redrawn
with modifications from Flynn (1967, p. 59).

A particularly valuable feature of Flynn’s model is

that, in his text, he explicitly specifies the neural loci
for many of his mechanisms. The patterning mechanism
is located in the hypothalamus; and at least part of the
inhibiting mechanism is located in the hippocampus.
This is one of the earliest models to identify the
hippocampus with a behavioral inhibition system.

Gray 1967, 1970 - Barbiturate as marker

Figure 4. Electrode placements producing the two forms Following on to some extent from Miller’s use of
of display shown in Figure 3. Note that there appear to be barbiturate drugs and taking a systems approach of the
two systems that run in parallel through the hypothalamus. type advocated by Flynn, Gray used barbiturates as
Open triangles – attack with display. Filled triangles –
quiet biting. From Flynn (1967, p.55), with permission. © markers for systems that mediate anxiety. He concluded:
Rockefeller University Press, 1967. Originally published in “there is a single physiological system which
Neurophysiology and Emotion (D.C. Glass, editor). mediates the effects of both punishment and frustrative
176 McNaughton

nonreward (the ‘fear = frustration’ hypothesis; Gray, (McNaughton & Sedgwick, 1978). To skip forward
1967), and … this system is antagonised by barbiturate in time, in terms of the historical sequence of this
drugs. … It should be noted that the reduction of paper, my laboratory later showed that all drugs
the effects of punishment … is confined to passive with an anxiolytic action (including ethanol,
avoidance situations… there is a remarkable similarity buspirone, imipramine, and fluoxetine) reduced
between the effects of lesions… to the hippocampus, theta frequency, whereas non-anxiolytics (anti-
and injections of amobarbital” (Gray, 1970, pp. 465- cholinergics, anti-serotonergics, anti-dopaminergics,
466, my italics). anti-noradrenergics) did not (Coop & McNaughton,
This statement is remarkable in that, at the time, 1991; Coop, McNaughton, & Lambie, 1991; Coop,
it was based on just one drug and only a handful of McNaughton, & Scott, 1992; Coop, McNaughton,
behaviors (Gray, 1967). Yet it has shown strong Warnock, & Laverty, 1990; McNaughton &
subsequent behavioral and neural predictive validity. Coop, 1991; Munn & McNaughton, 2008; Zhu &
McNaughton, 1991a, 1991b, 1994, 1995). Currently,
McNaughton 1977 - Theta frequency this test of anxiolytic action has no false positives,
no false negatives, and has demonstrated predictive
Observing a correlation and proving a cause is validity over three new drug classes (McNaughton,
not the same thing. Gray went on to link the similar Kocsis, & Hajós, 2007, for review).
effects of amobarbital and hippocampal lesions This and later work allows the common
on behavior to changes that the drug produced in behavioral profile of anxiolytics and hippocampal
hippocampal theta rhythm. The theta rhythm is a lesions to be explained by the fact that the
regular sinusoidal field potential that results from drugs impair theta modulated processing in the
the rhythmic burst firing of hippocampal neurons. hippocampal system.
It is the main electrical pattern of activity in the
hippocampus when a rat is performing voluntary Gray & McNaughton 1983 - Hippocampal profile
movements (Vanderwolf, 1969). Septal driving of
theta rhythm is affected by amylobarbitone (Gray & The link between anxiolytic drug action and the
Ball, 1970), but this effect failed to account for a hippocampus, and a much more detailed picture of
substantial proportion of the similarity in behavioral the nature of the core common behavioral deficits,
effects of anxiolytics drugs and hippocampal lesions was provided by a detailed review of the profile of
(McNaughton & Mason, 1980). However, as part of hippocampal lesion effects (Gray & McNaughton,
my PhD, I tested the effects of both amylobarbitone 1983). This provided a major foundation for Gray’s
and a range of benzodiazepines and found (Figure 6) model of the neuropsychology of anxiety (see next
that anxiolytics (but not non-anxiolytic depressants) section) when combined with his previous review of
reduced the frequency of hippocampal theta rhythm the effects of anxiolytic drugs (Gray, 1977). This was
further extended by Gray and McNaughton (2000),
where (Table 1) the predictive validity of the original
theory was demonstrated by the extension of the original
profile from classical (GABA-acting) anxiolytic drugs
to novel (serotonergic) ones, and to the inclusion (for
both classes of drug) of effects on the classic test of
hippocampal spatial processing, the Morris water
maze. The most important feature of the table was the
retention of the rule, originally noted in relation to
amylobarbitone, that the drugs and hippocampal lesions
change passive-avoidance-like behavior but not active-
avoidance-like behavior.

Gray 1982 model - The neuropsychology of anxiety

The main elements of Gray’s (1982) model of the

processing of anxiety are shown in Figure 7. The key
Figure 6. Classical anxiolytic drugs (barbiturates, point of this model, in relation to later models, is that
benzodiazepines) reduce the frequency of hippocampal theta the hippocampal formation (HF) is essentially seen
rhythm. Depressant drugs do not. From McNaughton and
Sedgwick (1978). ALP = alprazolam; AMY = amylobarbitone;
as a single core ‘comparator’ structure that processes
CDP = chlordiazepoxide; CPZ = chlorpromazine; DZP = information related to anxiety. Fear processes are
diazepam; HAL = haloperidol. located elsewhere, and the bottom left-hand part of the
Fear, anxiety and their disorders 177

Table 1. Comparison of the behavioral effects of hippocampal Rapoport 1989 - Obsession

lesions (HIP) and classical and novel anxiolytic drugs (ANX).
0 = no effect; + = behavior increased/performance improved;
Gray’s model is essentially unitary – attempting to
- = behavior decreased/performance impaired. Adapted from
Gray and McNaughton (2000) keep anxiety and fear each confined to a single place, or
at least to a homogenous system, in the brain. However,
Task HIP ANX even at the time, Gray recognised that there was a form
of anxiolytic-insensitive anxiety (or possibly fear)
Rewarded bar pressing, CRF 0 0 characterised by obsessionality and likely controlled via
Rewarded running, CRF 0 0 frontal cortical areas. Rapoport (1989) provided an even
more separate view of obsession. A cross-over design
Simultaneous discrimination 0 0 (Figure 8) showed that clomipramine was clearly more
effective than not only anxiolytics but also tricyclic anti-
Shock, skilled escape, active avoidance 0 0
panic drugs at treating obsession. This suggests that
Resistance to extinction + + obsession is a distinct function from simple anxiety, or
simple fear (at least as indexed by panic), with its own
Two-way active avoidance + + distinct neurology.
Non-spatial active avoidance + +

Rewarded bar pressing, intermittent RF + +

Successive discrimination - -

Spontaneous alternation - -

Rearing - -

Mazes (not radial arm) - -

Passive avoidance - -

Differential reinforcement of low rates - -

Spatial discrimination reversal - -

Water maze - -

model incorporates the main elements of Flynn’s model,

particularly the inhibitory function of the hippocampus.
Behavioral inhibition of flexible behavior (as opposed
to fixed action patterns) occurs via the Papez circuit.

Figure 8. Results of a drug cross-over experiment

comparing the effect of clomipramine (CMI, black circles)
with desipramine (DMI, gray circles) in the treatment of
obsession. Left-hand side: the group treated with CMI
shows clear reductions in obsessionality as measured by a
clinician-assessed global OCD score. Right-hand side: the
group switched to DMI from CMI shows an increase in
scores that returns them to values that would be expected
with continuous DMI. The group switched to CMI from DMI
shows a reduction in scores similar to that of the original
CMI group. With each pair of lines (solid, dashed) the slopes
are the same. Adapted from Rapoport (1989).

Rapoport (1989) provided considerable evidence

Figure 7. Gray’s (1982) model of the anxiety system (simplified to link the generation of obsessions with the cingulate
from his original diagram). The hippocampal formation (HF) cortex and the generation of compulsions with the
processes information related to anxiety. The theta rhythmic input
to the hippocampus is altered by anxiolytic drugs and this is how caudate nucleus. This not only makes it appear distinct
they alter the main functional outputs, particularly behavioral from simple fear and simple anxiety but also links it to a
inhibition (BI), see text. HYP = hypothalamus, c.f. Figure 5. range of disorders involving repetitive behavior.
178 McNaughton

Ledoux 1994 - Fear/Anxiety Model Blanchard & Blanchard 1990 -

Ethoexperimental analysis
A further complication for Gray’s (1982) model was
the development of theories of the amygdala that linked it These conclusions, then, naturally drew me to the
to both fear and anxiety. One particularly influential model work of Robert and Caroline Blanchard. They argued
is that of LeDoux (LeDoux, 1994). According to his view, strongly that typical controlled laboratory experiments
the role of the hippocampus was as a cognitive processor, fail to make clear why behavior occurs and that this is a
dealing particularly with contextual stimuli, whereas significant problem for theoretical development.
the main control of both fear and anxiety was located, “An additional and very different approach to
according to LeDoux, within the amygdala (Figure 9). This [emotion] stems from analysis of [the] possible functional
model both appears to ignore the extensive data discussed significance [of] characteristic behavior patterns seen in
above linking anxiolytic action with the hippocampus and response to important ecological demands (e.g., feeding,
appears to locate two quite distinct functional systems reproduction, defense) when animals are given the rather
within a single structure. It also places the hippocampus wide range of behavioral choices typical of most natural
at the top of a progressively more complex hierarchy of habitats, is called ethoexperimental analysis. It involves
processors. This seems unlikely in terms of phylogenetic a view that the functional significance of behavior
development with the hippocampus being relatively older attributed to anxiety (or other emotions) needs to be
and showing much less expansion than the neocortex. taken into account; ... [which] can be determined far more
efficiently when the behavior is studied under conditions
typical of life for the particular species”. (Blanchard &
Blanchard, 1990, p.125)

Figure 9. Ledoux’s model of the control of fear and anxiety

by the amygdala. The hippocampus is treated simply as a
processor of highly complex, contextual, stimuli. Adapted
from LeDoux (1994).

McNaughton 1989 - Evolutionary function as

defining an emotion
The idea of phylogeny brings us to a second strand
of theoretical development that was progressing in Figure 10. Schematic representation of the relation of behavior
parallel with the neuropsychological analyses. To to defensive distance. From Blanchard and Blanchard (1990),
maintain the coherency of this report, I deal with this with permission of the authors.
strand by taking a small step backward in time to
my analysis of the possible value of biological, and They, therefore, carried out experiments using a
particularly evolutionary, considerations in solving “visible burrow system” that allowed detailed analysis
the age-old problem of “what is an emotion” (James, of the normal day to day behavior of rats and of its
1884). My conclusion (McNaughton, 1989) was that interference by the introduction of a cat. For me, they had
emotions are best seen as being only partially coherent two particularly important findings. First, large amounts
at the neural, or control systems, level. The best means of behavioral variation could be understood in terms of
of characterising an emotion, I argued, was via its a hierarchy controlled by “defensive distance” (Figure
teleonomy (Pittendrigh, 1958), which can be treated as 10). Specific behaviors occurred at specific “distances”
an evolutionary function in a retrospective or historical – with this being an internal scale specific to each rat.
sense. That is, each emotion includes multiple reactions Behaviors proximal to the cat could be related to panic
that evolved separately without the need for a common (and were sensitive to panicolytic drugs), whereas more
neural control, but are perceived as coherent because distal behaviors could be related to phobia. Second, they
they have evolved for a common “purpose” (or it is distinguished categorically between fear-related (cat
better to say that the selection of the random mutations present) and anxiety-related behaviors (cat potentially
giving rise to them was shaped by the same, recurring, present) and discovered that the latter but not the former
fundamental situational requirements). were sensitive to anxiolytic drugs.
Fear, anxiety and their disorders 179

Graeff 1994 - Matching behavioral with quiescence (which is posturally distinct from freezing),
neural “levels” risk assessment and behavioral inhibition all contribute
to defensive approach (Blanchard & Blanchard, 1990;
For me, the most important advance in this whole Gray & McNaughton, 2000).
theoretical progression was provided by Graeff (1994)
in a paper in the Brazilian Journal of Medical and McNaughton & Corr 2004 - The 2D
Biological Research. He combined the hierarchical defense system
notion of defensive distance with the notion of levels
in the brain to produce a coherent mapping scheme The fundamentals of an essentially two-dimensional
between the two with charactertistic behaviors defining model of defense (combining defensive distance with
each level (Table 2). Some important features of this what can be seen as defensive direction, i.e., defensive
table are: 1) his treatment of an uncertain predator as approach versus defensive avoidance) were put together
being even further away than a distant but certain one, by me in a revision (Gray & McNaughton, 2000) of
producing a system tied to defensive distance; 2) his Gray’s 1982 theory. But this model was not symmetrical
mapping of the medial hypothalamus to fear (essentially and data continued to accumulate suggesting that it was
including Flynn’s earlier views), the septo-hippocampal incomplete. This, coupled with persistent questioning of
system to anxiety (essentially including Gray’s theory), the details of the theory in relation to human personality
and his mapping of the amygdala to anxiety (agreeing by Corr, led to our joint production of the symmetrical
with part of LeDoux’s theory); and 3) his mapping of 2D model of defense. This is shown with minor further
the periaqueductal gray to panic. updating (see legend) in Figure 11.
However, there were some features of this scheme To some extent this model is straightforward with
that appeared to me to be problematic. First, derived normal behaviours and clinical conditions assigned
from the Blanchards’ point of view, is the treatment to particular modules of a 2D system that combines
of anxiety as uncertain. The paradigmatic approach- Miller and Gray’s fear/anxiety distinction with Graeff’s
avoidance conflict studied by Miller involves no neural translation of the Blanchards’ hierarchical
uncertainty - just a balance between known appetitive ideas. However, superimposed on these modules is
and aversive drives. Second, is a departure from the diffuse noradrenergic and serotonergic innervation.
Blanchards’ formulation in treating anxiety as simply at The inclusion of these systems on anatomical grounds
a greater defensive distance than fear. They applied the allows the theory to account (with certain assumptions
concept of defensive distance to both anxiety and fear being made about receptor subtypes) for the behavioural
- and all anxious behavior, independent of defensive and therapeutic effects of a variety of drugs here. An
distance, is sensitive to anxiolytic drugs, whereas fear important feature of the serotonin system as shown
behavior is not. in Figure 11 derives from the views of Deakin and
This led me, via the requirement to provide a Graefff (1991) who see conditioned fear as inhibiting
sound teleonomic account of fear and anxiety, to the fight/flight reactions and so panic. This is linked to a
following simple definitions. Fear is all those behaviors, proposed dual action of 5HT enhancing most defensive
autonomic and other reactions, that have evolved in reaction (see + signs in Figure 11) but suppressing
response to the evolutionary pressure of removing the panic-related reactions in the periaqueductal gray (see –
animal from danger. Thus, freezing, fighting and fleeing sign in Figure 11). Further evidence for this position has
all contribute to defensive avoidance. Conversely, accumulated since then (Graeff & Del-Ben, 2008). This
and essentially opposite to fear, anxiety is all those antithetical effect of serotonin on the periaqueductal
behaviors, autonomic and other reactions, that have gray accounts for a range of otherwise anomalous
evolved in response to the evolutionary pressure of effects of serotonergic drugs and also for phenomena
allowing the animal to approach danger. Thus, defensive such as relaxation-induced panic (Graeff, 1994).

Table 2. Levels of defense, their neural substrate and related emotions (Graeff 1994)

Danger Behavior Emotion CNS

Uncertain Risk assessment Anxiety AM/SHS

Distal Freezing/escape Fear PAG-MR-SHS/MH

Proximal Fight/flight Rage/panic PAG

CNS, central nervous system; AM, amygdala; PAG, midbrain periaqueductal gray; MR, median raphe nucleus; SHS, septo-
hippocampal system; MH, medial hypothalamus.
180 McNaughton

defensive defensive defensive

avoidance distance approach
PREFRONTAL - OCD2 PREFRONTAL Social Anxiety -
VENTRAL STREAM deep obsession DORSAL STREAM complex cognition

+ +
ANTERIOR OCD1 POSTERIOR Agoraphobia
CINGULATE surface obsession CINGULATE cognition/rumination

+ +
AMYGDALA Phobia SEPTO-HIPPO- Generalised Amxiety
- avoid CAMPAL SYSTEM cognition/aversion

+ +
AMYGDALA Phobia AMYGDALA Generalised Amxiety
- arousal arousal/startle

+ +
MEDIAL Phobia - MEDIAL Focussed Anxiety
HYPOTHALAMUS escape HYPOTHALAMUS risk assessment

+
PERIAQUEDUCTAL Panic - PERIAQUEDUCTAL “Anticipatory Panic” -
GRAY explode/freeze GRAY defensive quiescence

– 5HT
NA Bus/BDZ/theta

Figure 11. A two-dimensional model of defense systems. There are two systems that differ in defensive direction: defensive
avoidance (fear) and defensive approach (anxiety). Both are innervated extensively by serotonin (5HT) and noradrenaline (NA).
Buspirone and other 5HT1A agonists (Bus), and benzodiazepines (BDZ) and other classical anxiolytic drugs do not affect the
defensive avoidance system and have their strongest effects, mediated by changes in theta rhythm, at the intermediate levels of
the defensive approach systems with weaker effects at the lowest and highest levels (stippled area, width indicating extent of
action). Normal defensive processes and associated pathologies are allocated to specific levels of each system. Adapted from
Gray and McNaughton (2000); McNaughton and Corr (2004).

Future developments • Worry/rumination: this is a clear feature of obsessionality

but the current model suggests that there may be both
If this paper were simply a history, it should stop at fearful and anxious forms of obsessionality. Further,
this point. However, the interest of history is whether there are clear data showing that although worry is a
we can learn from it. Also, I hope it is clear that this risk factor for anxiety disorder, worry and generalised
particular history is one of progressive questioning and anxiety (once they are present) are not strongly related
integration of the available data, producing theories that (Meyer, Miller, Metzger, & Borkovec, 1990).
become progressively more complete, with later theories
incorporating earlier ones rather than contradicting • Personality/neuroticism: Neuroticism is a risk factor
them. The development of the “2D model” is clearly still for both phobic and anxious disorders (and also
incomplete in a number of major respects so, as I said depression). That is, it predisposes both to disorders that
at the start, I hope this paper can be the kind of starting are sensitive to anxiolytics and those that are not. Does
point for some young researcher that Miller, Flynn and this involve some system such as the monoamine ones
Gray provided for me as an undergraduate. Issues that that provide diffuse input to the entire defensive system?
currently require obvious attention are as follows:
• Frontal cortex: It is important to note that the inclusion
• Neuroeconomics: what is the relation of the 2D theory of prefrontal cortex as a single box in Figure 11 ignores
to the theories of loss aversion, ambiguity aversion and the fact that it actually encompasses a substantial
risk aversion? There are good theoretical reasons for proportion of the brain. Disentangling the contribution
seeing loss as orthogonal to approach and avoidance of all its different areas can potentially answer many or
(for example, avoiding loss can produce approach). all of the previous bullet point questions.

• Uncertainty: what is the role of uncertainty of the type • Stress: the hippocampus is a key structure within
emphasised by the Blanchards? It is clearly not the basis the anxiety control network. How is this related to
for distinguishing anxiety from fear. However, uncertainty the fact that the hippocampus has one of the highest
is often a factor in generating anxiety – does this have concentrations of corticosterone receptors in the brain
some direct relation to, for example, ambiguity aversion? and is a key structure for the negative feedback control
Fear, anxiety and their disorders 181

of corticosterone and is involved in post-traumatic stress limbic site of action of minor tranquilizers. In L. L. Iversen, S. D.
disorder and depression? Iversen, & S. H. Snyder (Eds.), Handbook of psychopharmacology.
Vol 8. Drugs, neurotransmitters and behaviour (pp. 433-529). New
York: Plenum Press.
There are clearly many more questions to be asked. Gray, J. A. (1982). The Neuropsychology of Anxiety: An enquiry
in to the functions of the septo-hippocampal system. Oxford:
I hope this paper will help you frame the questions and Oxford University Press.
find their answers. Gray, J. A., & Ball, G. G. (1970). Frequency-specific relation between
hippocampal theta rhythm, behavior and amobarbital action.
Science, 168, 1246-1248.
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was my undergraduate teacher, unofficial advisor Anxiety: An enquiry into the functions of the septo-hippocampal
to my PhD and collaborator and co-author for more system. Oxford: Oxford University Press.
than 30 years. To my postgraduate students who did Hinde, R. A. (1966). Animal behaviour. New York: McGraw-Hill
Book Company.
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American, 270, 50-59.
Coop, Damon Mitchell, Elizabeth Money, Estella McNaughton, N. (1977). Exploration, frustration and the
Quintero, Gail Tripp, Gemma Irvine, Ian Kirk, electrophysiology of the septohippocampal theta system in the rat. 
Kiran Panickar, Mary-Anne Woodnorth, Ming Ruan, PhD, Southampton University.  
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