# Panic Disorder: Is the PAG Involved?

Authors: Cristina Marta Del-Ben; Frederico Guilherme Graeff
Journal: Neural Plasticity
 (2009)

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## Abstract

Data from studies with humans have suggested that abnormalities of midbrain structures, including the periaqueductal gray matter (PAG), could be involved in the neurobiology of panic disorder (PD). The electrical stimulation of the PAG in neurosurgical patients induces panic-like symptoms and the effect of drugs that are effective in the treatment of PD in the simulation of public speaking model of anxiety is in agreement with data from animal models of PD. Structural neuroimaging studies have shown increases in gray matter volume of midbrain and pons of PD patients. There is also evidence of lower serotonin transporter and receptor binding, and increases of metabolism in the midbrain of PD patients. Nevertheless, these midbrain abnormalities can not be considered as specific findings, since neuroimaging data indicate that PD patients have abnormalities in other brain structures that process fear and anxiety.


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## Body

## 1. Introduction

Panic disorder (PD) is a
common and incapacitating mental disorder characterized by the recurrence of spontaneous
panic attacks, followed by a persistent concern about having additional attacks,
worry about the implications of the attack or its consequences, and a
significant change in the behavior related to the attacks. A panic attack is
characterized as a discrete period of intense fear or discomfort, in which
several symptoms, such as palpitations, pounding heart, or accelerated heart
rate; sweating; trembling or shaking; sensations of shortness of breath or
smothering; feeling of choking; chest pain or discomfort; nausea or abdominal
distress; feeling dizzy, unsteady, lightheaded, or faint; derealization or
depersonalization; fear of losing control or going crazy; fear of dying;
paresthesias; chills or hot flushes, develop abruptly and reach a peak within
10 minutes. The symptoms are not related to substance abuse or general medical
condition and are associated with a significant impairment of global
functioning. Around 2/3 of patients with PD will also develop agoraphobia,
which is defined as an anxiety about being in places or situations from which
escape might be difficult, or embarrassing; or in which help may not be
available in the event of an unexpected or situationally predisposed panic
attack. Agoraphobic fears typically involve characteristic clusters of
situations that include being outside the home alone, being in a crowd or
standing in a line, being on a bridge, and traveling in a bus, train, or
automobile [1].Several brain structures
that organize defensive reactions and represent the neural substrate of fear
and anxiety have been implicated in the functional neuroanatomy of PD. Among those
are prefrontal regions, amygdala, hippocampus, and parahippocampal area,
hypothalamus, thalamus, and the periaqueductal grey matter (PAG) (for a recent
review; see [2]). In regard to the latter region, animal studies have shown
that electrical and chemical stimulations of the PAG cause urgent defensive
reactions, such as freezing, fight, or flight. The same responses occur when the animal is
faced by a clear and near threat, for instance, a predator [3]. Therefore, the
PAG has been implicated in the defensive reaction to proximal threats, and drugs
that increase the serotonergic function and are effective in the treatment of
PD are able to reduce behaviors normally observed with the stimulation of the
PAG (reviewed in [4]). Although other neurotransmitters, such as
cholecystokinin [5] and glutamate [6], also appear to regulate
fear/panic-related defensive behavior, the main focus of this review will be on
serotonin (5-HT) since this is the main neurotransmitter affected by the drugs clinically
used for the treatment of PD.Even though the evidence
that supports the involvement of the neurocircuitry underlying defensive
reactions in normal and pathological fear and anxiety has mainly been obtained
with preclinical research, data from studies with humans also give support to
the concept that structural and functional abnormalities in midbrain
structures, such as the PAG, could be involved in the neurobiology of PD.
Several reviews (e.g., [2]) have brought together animal findings showing the
role of PAG in fear reactions and defensive behavior to proximal threats, but data
coming from studies with human beings have not been completely explored. Therefore, the focus of this review is on
results from human studies, including healthy volunteers and patients with PD, which
provide evidence for a participation of the PAG in the pathophysiology of PD.


## 2. Symptomatic Homology

A pivotal evidence for the
involvement of midbrain structures in PD came from the induction of panic-like
symptoms by electrical stimulation of the PAG in neurosurgical patients. Awaked
patients submitted to the stimulation of the PAG report feelings of terror or
impending death, desire to flee, palpitation, and respiratory arrest or
hyperventilation [7–9]. The remarkable similarities between the effects of
PAG electrical stimulation in neurosurgical patients reported above and the
symptoms that occur during a panic attack led the Brazilian psychiatrist Valentil
Gentil to suggest a participation of the PAG in the neurobiology of panic
attacks. Commenting on the changing
in the behavior of rats due to the stimulation of the dorsal PAG, Gentil
remarked, “I believe that (this animal) model is particularly useful for
the understanding of the pathophysiology of panic attacks, especially the
“spontaneous” attacks. … (Bearing in mind that) the panic attack is a very
primitive behavior … the isomorphic validity of the central gray's (PAG) poorly
organized responses to γ-aminobutyric acid (GABA-A) antagonists and electrical
stimulation to the maladaptive flight behavior of full-blown panic seems
high” [10]. Further, the phenomenological resemblance between panic
attacks and the effects of the electrical stimulation of the PAG in both humans
and animals has been systematically explored [11, 12], the main results being summarized
in Table 1.Table 1
Phenomenological similarities between panic attacks and effects of electrical stimulation of the
periaqueductal gray matter (PAG) in humans and rats. Adapted from Jenck et al. [11] and
Schenberg et al. [12].
Spontaneous panic attackStimulation of dorsal PAG in humansStimulation of dorsal PAG in ratsIntense fear or discomfortPanic, terror——Intense distressAversionPalpitations, pounding heart, or accelerated heart rateTachycardiaTachycardiaSweatingSweating—Trembling or shakingSensation of vibration—Sensations of shortness of breath or smothering—Tachypnea—HyperventilationHyperventilation—Apnea—Chest pain or discomfortChest and heart pain—Nausea or abdominal distressBladder voiding urgeMicturation——DefecationFear of dying“Scared to death”Escape responsesChills or hot flushes“Burn/cold” sensations—Although the similarity
between the symptoms of a spontaneous panic attack and the effects of
electrical stimulation of PAG is often cited as a face-validity criterion for
implicating the PAG in PD, information obtained from awaked patients about the
subjective and somatic responses provoked by stimulation of PAG is  rare in the recent literature. An
exception is the work carried out by Green et al. [13], using deep brain
stimulation, who have
obtained results similar to those reported by Nashold et al. [7], four decades ago. In
the procedure of deep brain stimulation, electrodes are implanted permanently
into specific areas of the brain. The electrodes are connected by wires under
the skin to a generator allowing continuous electrical stimulation of specific
brain areas. In this study, patients had electrodes implanted inside the PAG to
control neuropathic pain. It has been observed that electrodes placed more
dorsally in the PAG increased systolic and diastolic arterial blood pressure,
what did not occur with electrodes placed more ventrally in the PAG.  Moreover, two patients with dorsal electrodes
reported nausea, sweating, and anxiety, symptoms commonly observed during a
spontaneous panic attack. Although this issue has not been completely
established, there is some evidence pointing to an association between PD and
hypertension. In this regard, it has been proposed that both conditions would
share a dysfunction of brainstem structures that regulate the autonomic nervous
system and are inhibited by 5-HT [14].


## 3. Experimental Anxiety in Humans

Aiming to conciliate seemingly
conflicting results derived from animal studies about the role of 5-HT in
anxiety, it has been proposed that 5-HT projections from the dorsal raphe
nucleus (DRN) facilitate inhibitory avoidance in limbic forebrain structures, predominantly
amygdala and frontal cortex, while inhibit escape in the dorsal PAG [12]. This
arrangement may have adaptive value, since it allows inhibition of fight/flight
behavior in situations where threat is only potential or remote.More recently, Lowry et
al. [15] have shown that the 5-HT projections to cortical and limbic structures
arise from a neuronal set located in a specific part of the caudal DRN, which
is particularly sensitive to stressful stimuli. The rostral projections from
these neurons seem to constitute a mesocorticolimbic 5-HT system that modulates
defense. Based on correlations between the pharmacological efficacy of
antidepressants and anxiolytic drugs in anxiety disorders and the results
obtained in experimental models of anxiety in humans (discussed below), it has
been further suggested that generalized anxiety disorder (GAD) would be related
to the inhibitory avoidance and conditioned anxiety, whereas PD would be
related to the escape response and innate fear [16]. A schematic representation
of the hypothesis on the dual role of 5-HT in anxiety and defense is
represented in Figure 1.Figure 1
Schematic
representation of the dual role of serotonin on fear and anxiety, according to
Deakin and Graeff theory.This theoretical model has been systematically
tested using two experimental procedures that generate anxiety in human beings:
the simulated public speaking (SPS) and the skin conductance response (CSCR)
tests (for a review; see [17]). It is
important to note that this experimental approach is different from that used
in pharmacological challenges aimed at provoking a panic attack in vulnerable
individuals. In this case, the most used are the infusion of sodium lactate and
the inhalation of CO2. Both challenges induce panic attacks in
around 60 to 80% of panic patients, as compared to 0 to 20% of healthy
controls. This seems to be a very specific response, since these challenges do
not cause panic attacks in phobic or obsessive compulsive patients. Moreover,
pharmacological studies have evidenced that antidepressant treatment decreases
the vulnerability of panic patients to lactate and/or CO2 [18]. The
similarities between the effects of lactate and CO2 led to the
hypothesis that both challenges have a common mechanism of action, causing an
intraneuronal hypercapnia in brain areas that are stimulated by CO2 during suffocation. The sensitivity of such suffocation alarm system would be abnormally
heightened in PD patients [19].Basically, the SPS test consists in
the preparation and performance of a speech in front of a videocamera, with the
participant seeing his/her own image on a TV screen. Subjective and physiologic
measures of anxiety are taken before, during and after the speech. The emotional
state induced by SPS is supposed to be species-specific fear, given that fear
of speaking is highly prevalent in the general population [20] and occurs in
healthy persons, irrespective of their personality trait to react with more or
less anxiety to stressful situations [21]. Pharmacological studies have shown
that drugs that facilitate 5-HT function decrease, whereas drugs that impair
5-HT function increase speaking fear [17]. On the other hand, the CSCR test is
based on classical conditioning theory, consisting in the presentation of 10
neutral tones (habituation phase), followed by a neutral tone paired with a
loud white noise (acquisition phase) and by the representation of 10 neutral
tones (extinction phase). During the procedures, measures of skin conductance
are taken. Drugs that increase 5-HT tend to facilitate conditioning [17].Several 5-HT acting
drugs have been assayed in these tests. For instance, a single dose of chlomipramine
[22] and nefazodone [23] administered to healthy volunteers increased the fear provoked
by the SPS, and this effect has been related to the clinical worsening observed
at the beginning of the treatment with antidepressants [24–26]. While some
animal studies have shown an increase in cortical extracellular level of 5-HT
following acute administration of antidepressants [27–29], others have
shown a greater increase of extracellular 5-HT in the raphe nuclei than in the
neocortex [30]. If so, a single dose of an antidepressant would preferentially
increase the concentration of 5-HT near the cell bodies of serotonergic
neurons, which would activate somatodendritic 5-HT1A autoreceptors, reducing
neuronal firing [31] and, consequently, leading to a decrease in the release of
5-HT in the synaptic cleft. Therefore, the fear-enhancing effect of a single
dose of antidepressants in SPS could be due to a lack of 5-HT inhibition of
brain systems that generate panic attacks, likely to be localized in the dorsal
PAG [4, 32].In agreement with the
hypothesis about the dual role of 5-HT in fear and anxiety, ritanserin,
a 5-HT receptor antagonist, has shown opposite effects in the SPS and CSCR
tests, prolonging the fear induced by SPS and decreasing conditioned skin
conductance responses [33]. These results resemble reported clinical results
with ritanserin, showing improvement of GAD [34], but a tendency to aggravate
PD [35, 36]. To the opposite direction, the 5-HT releaser d-fenfluramine has
been shown to reduce SPS-induced fear [37] and to improve PD [38, 39]. In contrast,
d-fenfluramine tended to increase the amplitude of conditioned skin conductance
responses, suggesting an anxiogenic-like effect [37].Hence these pharmacological results with
experimentally-induced fear and anxiety in humans are in agreement with the
hypothesis that 5-HT enhances anxiety, which can be evaluated by the CSCR test,
whereas inhibits fear, which can be assessed by the SPS test. The former effect
would be related to the action of 5-HT on forebrain structures and the latter
to its action on dorsal PAG. It has been well demonstrated that the chronic use
of drugs that increase the availability of serotonin in the synaptic cleft is effective
for the treatment of PD [40] and it has been proposed that the reduction in the
occurrence of panic attacks with the use of antidepressants could be due to enhancement
of the inhibitory action of serotonin on the PAG [4].


## 4. Panic Patients and Experimental Models of Anxiety

It is important to note that the SPS
is not taken as a model of panic attack and it is not expected to provoke panic
attacks in susceptible individuals. The possible association between the
experimental model and the mental disorder is based on the rationale that
public speaking would engage the neural substrates involved in the process of
innate fear, which would be abnormal in PD.Therefore, if the predictions derived from
pharmacological studies with the human tests discussed above are correct, it would
be expected that patients with the diagnosis of PD and healthy volunteers would
perform differently in the SPS, but not in the CSCR test, given that the former
would engage the brain mechanisms implicated in the neurobiology of PD, but the
latter would not.Aiming to test this hypothesis, we
submitted panic patients free of treatment to both models of anxiety [41]. As
predicted, controls and panic patients showed a similar response to CSCR. In contrast,
during the SPS test, panic patients demonstrated higher levels of subjective anxiety
than healthy volunteers from the beginning to the end of the experimental session
but were less responsive to the speaking challenge. The profile of the
subjective response of panic patients to the SPS test bears a resemblance to
the effect of metergoline, a nonselective 5-HT-receptor blocker, given to
healthy volunteers. Metergoline enhanced the subjective anxiety before and
after the speech, but not during the preparation or the performance of the
speech [42]. These results were in agreement with the suggestion that an
impairment of the 5-HT function leading to a reduced of the inhibition of PAG
may be present in the neurobiology of PD [16].Using a similar protocol [43, 44], new
groups of symptomatic panic patients and healthy controls were submitted to the
SPS test. In addition, a third experimental group composed by panic patients
who had become nonsymptomatic after long-term pharmacological treatment with
antidepressant drugs was added. The aim was to verify whether the differences
between healthy subjects and PD patients, if replicated, would remain after recovery,
being thus related to a vulnerability trait, or otherwise decrease, and
therefore being related to the clinical condition (state).As can be seen in Figure2, and in
agreement with the former study, symptomatic drug free panic patients had more subjective
anxiety during the experimental session than controls, despite the changes
introduced in the procedures to minimize differences in expectancy and
familiarity that might enhance or decrease initial anxiety, respectively. A
more prolonged period of habituation decreased the anxiety in all groups, but
the response to the SPS challenge was smaller in symptomatic patients than in
normal controls. Moreover, nonsymptomatic patients stand between controls (below) and symptomatic panic patients (above) with regard to subjective anxiety, measured by
the visual analogue mood scale (VAMS) and to bodily symptoms, measured by the total score of the bodily symptoms scale
(BSS). Therefore, these measures seem to be related to the magnitude of
clinical manifestations of PD rather than to a vulnerability trait, since they
were affected by pharmacological treatment.Changes in
anxiety (VAMS, upper panel), bodily symptoms (BSS, mild panel), and salivary
cortisol levels (lower panel) induced by simulated public speaking (SPS) in
symptomatic panic patients (SPD), nonsymptomatic patients (NSPD), and healthy
controls. The phases of the experimental session are beginning (B), pretest
(P), anxiety during speech preparation (A), performance anxiety during the
speech (S), and final (F). Points in the curves indicate mean values and
vertical bars the S.E.M. Figure modified from Garcia-Leal et al. [43] and
Parente et al. [44]. * = significant difference (P<.05) from
controls.
(a)(b)(c)This study has also shown a significant
decrease in the level of salivary cortisol from the initial to the pretest
phases of the experimental session, in parallel with habituation of the
anticipatory anxiety induced by the experimental setting. Additionally, a
positive correlation between levels of subjective anxiety and of salivary
cortisol has been found in control subjects at the initial phase of the
experimental session. In contrast, salivary cortisol did not increase during
the 60 minutes following the end of the speech, neither in patients, nor in
controls, despite the levels of anxiety measured during speech preparation and
performance being at least as high as those at the onset of the experimental session.
Therefore, the SPS task does not seem to increase cortisol secretion. In
agreement with these results, neither spontaneous panic attacks [45] nor the
electrical stimulation of the dorsal PAG of the rat [46] activates the
hypothalamic-pituitary-adrenal axis.A final remark about the possible
abnormal processing of innate fear in PD
has come from a study carried out in our laboratory with patients with social
anxiety disorder (SAD) submitted to the
SPS test (MC Freitas, A Santos Filho, F Osório, SR
Loureiro, CM Del-Ben, AW Zuardi, FG Graeff, JAS Crippa, unpublished results).
SAD and PD are different anxiety disorders, but they keep some similarities, such
as the response to the treatment with antidepressants that act on 5-HT
function. However, in comparison to healthy controls, SAD patients have shown a
larger enhancement of the fear induced by the SPS, what is different from the
results obtained with PD patients. For that reason, we could speculate that the
lower fear response induced by SPS could be specific to PD and related to
abnormal functioning of brain structures involved in the process of innate fear.


## 5. Neuroimaging Data

As discussed earlier, evidence
from preclinical studies suggests that the neural substrates involved in the
defensive reactions to environmental threats of mammalian species could be
implicated in the pathophysiology of PD. The main brain structures possibly involved
in the neurobiology of PD encompass the prefrontal cortex, anterior cingulated
cortex, hypothalamus, amygdala, hippocampus, and the midbrain, including the
periaqueductal grey matter [2].Structural neuroimaging
studies, using magnetic resonance imaging (MRI), have shown that anatomical
brain abnormalities, particularly in the temporal lobes, are more frequently
observed in panic patients than in controls [47–49]. A quantitative
evaluation of specific brain structures has also demonstrated differences
between PD patients and healthy volunteers, characterized by a reduction of the
volume of temporal lobes, amygdala, and hippocampus (trend) in PD patients
compared to controls [50–52].Voxel-based morphometry
(VBM) is a more sophisticated approach of structural neuroimaging that provides
an automated method of segmentation into gray matter, white matter, and
cerebrospinal fluid (CSF) compartments and allows the investigation of
differences in regional volumes along the whole brain [53]. Using the VBM technique,
Protopopescu et al. [54] have shown an increase in gray matter volume of the
midbrain and rostral pons of the brainstem of panic patients compared with
healthy controls. At a lower significance threshold, they have also reported
increased ventral hippocampal and decreased regional prefrontal cortex volumes
in PD.In a recently published
study [55], we have also found a relative increase in gray matter volume of midbrain
and pons (on left) in panic patients. As it can be seen in the Figure 3, additional
findings include increase in gray matter volume of the left insula and left
superior temporal gyrus and a relative gray matter decrease in the right
anterior cingulate cortex. The anterior insula has close connections to the
amygdala and, together with the ventromedial prefrontal cortex, anterior
cingulate cortex, hypothalamus, and periaqueductal gray matter, is considered
as part of a network that modulates the identification of, and the response to,
aversive or threatening stimuli [56] and has been proposed as a key structure involved
in the neurobiology of anxiety disorders [57]. In particular, the increase of
gray matter volume of midbrain is in agreement with the proposition that periaqueductal
gray matter would be implicated in the pathophysiology of PD as well in the
antipanic action of antidepressant drugs [2, 4, 16].Statistical
parametric maps displaying significant differences in gray matter volume of PD
patients (n=19) relative to healthy
controls (n=20). (a) Increased gray matter volume, (b) decreased gray matter volume. 1=left
insula; 2=left superior temporal gyrus; 3=midbrain; 4=right anterior cingulate.
(a)(b)Functional neuroimaging
studies have also contributed to a deeper understanding of the neural
substrates of PD. In a seminal work, using positron emission tomography (PET),
Reiman et al. [58] have found
abnormalities in the parahippocampal gyri, characterized by an abnormal
asymmetry (left less than right) of the regional cerebral blood flow (rCBF),
observed, during rest, in panic patients vulnerable to the lactate challenge.
Further functional studies have also shown alterations in the metabolism or
blood flow of hippocampus and parahippocampal areas of panic patients [59–65] and this seems to be the most consistent finding across the
studies with functional neuroimaging in PD. Other areas implicated in the
pathology of PD by functional studies are prefrontal cortex [59, 60, 65], anterior
cingulate gyrus [62, 65], superior temporal cortex [61, 62], amygdala [63, 64], hypothalamus
[62], and thalamus [63, 64].Considering that the PAG
is a small brain structure, the detection of dysfunctions of its metabolism is
not straightforward, due to limitations of the neuroimaging technique itself. Even
so, some studies have reported abnormalities in the midbrain of panic patients.Just before being
submitted to a pentagastrin challenge, panic patients, compared with healthy
volunteers, have shown an increase of blood flow in parahippocampal gyrus, left
hippocampus, right temporal lobe, orbitofrontal cortex, anterior cingulate
gyrus, hypothalamus, thalamus, and midbrain, “probably” PAG [62]. Interestingly, bilateral
insula, inferior frontal gyrus, and right amygdala have shown abnormalities in
their metabolism in the opposite direction, with a decrease of blood flow, what suggests that the inhibitory function of forebrain structures over phylogenetically more primitive structures, such as the PAG, would be impaired in panic patients.In the same direction,
Sakai et al. [63, 64] have found higher levels of glucose uptake in the midbrain,
caudal pons, and medulla in panic patients than controls. They also have shown
an increase of the metabolism in bilateral amygdala, hippocampus, and thalamus.
In a further study, the same group [65] has shown a decrease of glucose uptake
in the right hippocampus, left anterior cingulate, left cerebellum, and pons
and an increase of glucose uptake in bilateral medial prefrontal cortices in panic
patients that had shown clinical improvement after a cognitive-behavioral
therapy intervention. These changes in the brain metabolism with the treatment with
antidepressants or cognitive-behavioral therapy have not been found in previous
studies [60, 66]. More interestingly for this review is the fact that they have demonstrated a correlation between the percent changes in glucose
utilization in the midbrain “around PAG” and those of the number of panic
attacks during the 4-week period before each scan, which shows a direct
relation between PAG metabolism and the occurrence of panic attacks.As discussed above, serotonin
has been largely implicated in the pathophysiology of panic disorder, and some
evidence from neuroimaging studies suggests alterations in the 5-HT system of
PD patients. The intravenous administration of d-fenfluramine, which induces
the neuronal release of serotonin, has provoked a decrease of blood flow in the
left posterior parietal-superior temporal cortex in panic patients [66]. A
lower volume of distribution of a selective radioligand of serotonergic receptors
5-TH1A type has been described in the anterior cingulate, posterior
cingulate, and raphe of nonmedicated panic patients relative to controls [67].
A significant decrease in the serotonin transporter (5-HTT) binding in the
midbrain, temporal lobes, and thalamus of symptomatic panic patients free of
medication has also been reported [68]. However, in comparison to patients with
current symptoms, panic patients in remission and free of medication have
normal 5-HTT binding properties in the midbrain and in the temporal regions but
still show significantly lower thalamic 5-HTT binding. Considering all the patients’ (current and in
remission) significant negative correlations between the severity of panic
symptoms and the midbrain, temporal lobe, but not thalamic 5-HTT binding, has also been
demonstrated [68].These abnormalities in the
binding of 5-HT receptors and transporter in midbrain areas are in agreement with the hypothesis that
the occurrence of panic attacks would be caused by spontaneous activations of
the fight/flight response organized by the PAG and inhibited by 5-HT [16].Although few studies have
applied functional magnetic resonance imaging (fMRI) in panic patients so far,
most of them confirmed alterations in the brain areas previously supposed to be
involved in the neurocircuitary of PD. In a paradigm of mental imagery of
neutral, moderate, and high anxiety situations, panic patients have shown
increased neuronal activation in the inferior frontal cortex, hippocampus, and
anterior and posterior cingulate, extending into the orbitofrontal cortex
bilaterally, during the anxious blocks compared to neutral blocks [69]. Panic
patients have also shown significantly higher activation in left posterior
cingulate and left middle frontal cortices and a more pronounced asymmetry
(right > left) in parahippocampal regions in response to a threat-related
stimuli, in comparison to healthy volunteers [70]. Compared to healthy
controls, panic patients have demonstrated significantly less activation to
fearful faces in the cingulate cortex and the amygdala, bilaterally [71].For our knowledge, none of
these fMRI studies have reported functional alterations in the midbrain. This not only can be due to limitations
of the technique itself that do not allow the analysis of changes of fMRI
signal in such a small area but also can be related to the hypotheses underlying
the studies, which drive the choice of the paradigm of psychological activation
and determine the regions of interest where the possible alterations will be
looked for. For instance, in the light of the comprehensive view of the
neurobiology of anxiety and fear proposed by Deakin in Graeff [16] a suitable paradigm
to provoke enough haemodinamic response of midbrain areas would be related to
the process of innate fear in humans.In this regard, a very
interesting work carried out with healthy volunteers has brought some light to
this discussion. Mobbs et al. [72] have evaluated the effects on brain
activation of the distance of a virtual predator. In this paradigm,
participants could control the movements of a virtual prey (represented as a
dot) in a labyrinth presented on a video-screen, using a keyboard, aiming to avoid
a virtual predator (represented by a triangle) with the ability to chase,
capture, and inflict pain. In the case of the predator caught the prey, two
levels of pain represented by either one or three electric shocks administered
to one finger of the participant. When the predator was far from the prey, the haemodinamic
responses observed in the prefrontal cortex and lateral amygdala were more pronounced,
particularly when the expected shock intensity was low. In contrast, when the
predator was closer, the haemodinamic response shifted to the central amygdala
and the PAG, reaching the maximum of activation when the highest level of pain
was anticipated. Even more interesting, there was a positive correlation
between PAG activation and the reported subjective degree of dread and
decreased confidence of escape. These results give strong support to the role
of the midbrain PAG in proximal defense, and possibly panic, as early proposed [2, 14].


## 6. Conclusions

In accordance to results
coming from animal research, data from experimental models of anxiety,
pharmacological challenges, and neuroimaging studies carried out with healthy
volunteers and patients with PD point to the involvement of the PAG in the
neurobiology of PD. Nevertheless, these midbrain abnormalities cannot be
considered as specific findings, since neuroimaging data have also shown that
PD patients have changes in other brain structures that participate in the regulation
of fear and anxiety. In a more integrative approach, it is reasonable to
suppose that a dysfunction of PAG could be part of a global dysfunction that
affects a network of related brain structures, or even a consequence of other
dysfunctions, such as low 5-HT function, impairment of inhibitory efferent
pathways from rostral brain areas, or both. Further studies conciliating
biological vulnerability, environmental influences and, mainly, the
connectivity among different brain structures with a clear hypothesis-driven
approach are needed.



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