REVIEW

URRENT
C
OPINION

Can anxiety damage the brain?

Linda Mah a,b, Claudia Szabuniewicz b, and Alexandra J. Fiocco c

Purpose of review
Stress exacerbates mental illnesses such as depression but also appears to increase risk of dementia,
suggesting a common mechanism for development of stress-induced affective and cognitive impairment. The
purpose of this review is to address the question of whether anxiety damages the brain, and to identify
potential mechanisms for the link between stress and neuropsychiatric illness.
Recent findings
Anxiety disorders are associated with alterations in fear neurocircuitry such that bottom-up processes in
the amygdala which respond to threat are exaggerated, and regulation of these processes by the
prefrontal cortex (PFC) and hippocampus is impaired. Chronic stress exposure similarly alters fear
neurocircuitry by enhancing amygdalar functioning while causing structural degeneration in the PFC and
hippocampus thereby inhibiting PFC/hippocampus control over the stress response. Pharmacological (e.g.,
antidepressant medications) and nonpharmacological interventions (cognitive-behavioral therapy, exercise)
may reverse stress-induced damage in the brain.
Summary
Pathological anxiety and chronic stress lead to structural degeneration and impaired functioning of the
hippocampus and the PFC, which may account for the increased risk of developing neuropsychiatric
disorders, including depression and dementia. Longitudinal studies are needed to determine whether
reversal of stress-induced brain changes by interventions such as cognitive-behavioral therapy can reduce
risk of neuropsychiatric illness.
Keywords
anxiety, cognition, emotion regulation, hippocampal neurogenesis, stress

INTRODUCTION
Anxiety is a feeling of unease, nervousness, or worry
about an event with an uncertain outcome [1].
These subjective symptoms are often accompanied
by physiological signs of arousal, such as sweating,
trembling, dizziness, or a rapid heartbeat. Anxiety is
a normal part of life when it is occasional and
temporary, but can become pathological or a disorder when it is frequent or chronic and begins to
interfere with daily activities such as work, school,
and relationships. The terms anxiety, fear, and stress
are often used interchangeably, with the main
differences arising in the nature of the event that
elicits the emotional response and arguably, the
extent to which the response is appropriate or normal. Because anxiety is a feeling associated with an
imminent event or a hypothetical situation that
may or may not happen [2], it is often conceptualized as being a negative or maladaptive state. In
contrast, fear is typically defined as an emotional
reaction when confronted with immediate or perceived threat, and is considered to be vital to survival. But fear can also be pathological, as in the
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phobic disorders. Stress is typically conceptualized

as an adaptive response to a specific challenge or
demand, and its definitions emphasize physiological, in addition to emotional changes. Chronic
stress, however, is a pathological state that is caused
by prolonged activation of the normal acute physiological stress response, which can wreak havoc on
immune, metabolic, and cardiovascular systems.
Thus anxiety, fear, and stress are not distinct but
rather are inter-related, by virtue of common neuroendocrine and arousal mechanisms and an extensively overlapping neurocircuitry [3 ]. When
&

Department of Geriatric Psychiatry, University of Toronto, bRotman

Research Institute, Baycrest Centre for Geriatric Care and
c
Department of Psychology, Institute for Stress and Wellbeing Research,
Ryerson University, Toronto, Ontario, Canada
Correspondence to Linda Mah, MD, MHS, Rotman Research Institute,
Baycrest Health Sciences, 3560 Bathurst Street, BHC 738, Toronto,
ON, M6A 2E1, Canada. Tel: +1 416 785 2500 x3365;
e-mail: lmah@research.baycrest.org
Curr Opin Psychiatry 2016, 29:5663
DOI:10.1097/YCO.0000000000000223
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Can anxiety damage the brain? Mah et al.

KEY POINTS
Emotional memory

 Pathological anxiety and chronic stress increase risk of

neuropsychiatric disorders, including depression
and dementia.

Fear conditioning

Lateral PFC
control network

Extinction learning

 Chronic stress enhances amygdala function but leads to

deficits in emotion regulation as a consequence of
stress-induced impaired hippocampal neurogenesis and
structural degeneration of the PFC.

Medial PFC
Contextual regulation
of extinction memory

Hipp/parahippocampal gyrus
Excitatory

 These stress-induced changes may contribute to

development of affective and cognitive disorders.
 There is some evidence that PFC function and
hippocampal neurogenesis may be restored with
pharmacological and
nonpharmacological interventions.

functioning optimally, these systems serve to direct

attentional resources toward salient information in
the environment and mobilize appropriate behaviors in response. Thus, this review addresses the
question of whether anxiety damages the brain
and identifies potential mechanisms for this
putative causal relationship by integrating findings
from animal models of stress and fear conditioning
and from neuroimaging studies of stress and
anxiety in healthy individuals and in clinical populations. We begin by reviewing the neurocircuitry of
fear and anxiety and provide an overview of how
this neurocircuitry is altered in clinical anxiety disorders. We then review the neurocircuitry of the
stress response, discuss the impact of chronic stress
on the brain, and conclude by reviewing some
recent findings on the effect of antianxiety interventions on the brain.

NEUROCIRCUITRY OF FEAR AND

ANXIETY
Detection of threat or other salient information in
the environment and generation of autonomic
arousal and emotions such as fear and anxiety in
response to threat are mediated by a bottom-up or
ventral neural system. This system includes the
amygdala, insula, ventral striatum, hypothalamus,
periadequeductal grey, and ventral regions of the
anterior cingulate cortex (ACC) and of the prefrontal cortex (PFC), specifically ventromedial PFC
(vmPFC) and orbitofrontal cortex [4]. The amygdala
plays a central role in this circuit. The amygdala
selectively attends to threat and is essential for
expression of fear. It also plays an essential role in
fear conditioning by learning cues that predict
adverse events [5]. This ventral network has been

Emotion regulation

Inhibitory

Amygdala
Key brain structures in neurocircuitry of emotion regulation impacted by stress

FIGURE 1. Key structures in neurocircuitry of fear and

anxiety (amygdala, medial prefrontal cortex, hippocampus)
which are impacted during exposure to chronic stress. These
structures mediate fear conditioning and extinction and also
serve to regulate the stress response. Hipp, hippocampus;
PFC, prefrontal cortex.

delineated based on animal models of fear conditioning and extinction [5,6], lesion studies
[7,8,9 ], and human neuroimaging studies of fear
and anxiety (Fig. 1) [10,11].
Top-down cognitive processes, or a dorsal neural system, regulate these emotional responses
through cognitive appraisal of the potential threat
and inhibition of autonomic and emotional processes when they are no longer appropriate for the
situation [12,13]. Both the PFC and the hippocampus play important roles in downregulation of
bottom-up processing of threat. Regulation of
emotional responses such as fear and anxiety may
be achieved through voluntary or involuntary subprocesses. Voluntary or conscious subprocesses include
suppression of emotion, distraction from the threatening stimulus, and reappraisal of the threat or
emotion stimuli. These voluntary processes are supported by dorsal and lateral regions of the PFC and
ACC [dorsolateral PFC (dlPFC), ventrolateral PFC
(vlPFC), dorsal ACC, dorsomedial PFC (dmPFC)]
[1416]. Involuntary, automatic, or unconscious
processes include extinction of previously conditioned fear responses, inhibition of autonomic
responses and physiological arousal, automatic redirection of attention, and automatic cognitive
appraisal and reappraisal. The processes of extinction and inhibition of autonomic responses are
mediated primarily through interactions between
the amygdala and vmPFC [17,18]. Functional neuroimaging studies in healthy individuals also demonstrate that the ability to decrease negative affect is
subserved by amygdala-vmPFC coupling [19]. In
contrast, automatic redirection of attention away

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Geriatric psychiatry

from threat appears to depend on activation of the

rostral ACC [20].
Although the hippocampus plays an important
role in memory formation, it also serves to regulate
emotions through contextual extinction during fear
conditioning. In contrast to the amygdala which
processes cues predicting a threatening or aversive
stimulus during fear conditioning, the dorsal
hippocampus relays contextual information about
the specific threat cue through interactions with
the amygdala and the vmPFC [21,22]. The dorsal
hippocampus encodes contextual information or
cues relevant to the threat which is then retrieved
when subsequently presented with the stimulus
[23]. This allows the organism to discriminate threat
from safety cues and appraise the relative threat
level of the stimulus [24 ]. In animal models of fear
conditioning, for example, when rats are presented
with a tone predicting a shock, they learn to fear
the tone cue as well as the place (context) where the
tone-shock pairings occurred. This ability to discriminate between features that signal threat versus
those that indicate safety may contribute to automatic cognitive appraisal and reappraisal as a means
to regulate emotions. In humans, there appear to be
dissociable contextual effects of the hippocampus
on medial prefrontal cortex (mPFC) pathways with
the dmPFC mediating the effect of hippocampus on
amygdala activity during fear renewal (reinstatement of conditioned fear following extinction)
and the vmPFC partially mediating the effect of
hippocampus on the amygdala during extinction
recall [25 ].
In summary, a simplification of fear and anxiety
neurocircuitry is that the amygdala (bottom-up/
ventral neural system) functions to detect threat
and generate emotions such as fear and anxiety,
whereas the mPFC and hippocampus (top-down/
dorsal ventral system) function to downregulate
the amygdala. Emotion regulation is achieved when
activity of the amygdala is balanced with the activity
of the mPFC and hippocampus.
&

hippocampus) is hypoactive. A wealth of evidence

indicates that anxiety disorders are associated with
increased sensitivity to threat or negative information in the external environment, such that
attention is selective for threat, and exposure to
threat is associated with enhanced amygdala
activity. This has been demonstrated in panic disorder [26,27], social anxiety disorder (SAD) [28,29],
simple phobias [3032], generalized anxiety disorder (GAD) [3335], and posttraumatic stress disorder (PTSD) [3638]. There is also evidence of
impaired extinction learning [39], reduction of
mPFC activity [28,29,34,4042], and decoupling
of the amgydala and mPFC in these disorders
[43,44 ,45 ], suggesting decreased PFC control over
the amygdala and other region in the ventral neural
system. Anxiety disorders are also associated with
the tendency to overgeneralize or generalize fear
across stimuli, events or contexts because of
impaired ability to discriminate between threats
versus safety cues, that is, impaired discriminative
conditioning. Deficits in discriminative conditioning have been demonstrated in GAD [46 ], panic
disorder [47], PTSD [39,48 ] and social phobia [49].
In PTSD, impaired discriminative conditioning is
associated with reduced hippocampus volume
[50,51]. Reduced contextual control of extinction
by the hippocampus, leading to reinstatement of
conditioned fear that was previously extinguished,
or fear renewal is suggested as a mechanism for
development of anxiety disorders [52].
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FUNCTIONAL NEUROANATOMY OF
ANXIETY DISORDERS
The hallmark of anxiety disorders is impaired ability
to regulate emotional responses to perceived threat.
This may occur because of a reduction in threshold
for activation of the amygdala and other limbic/
subcortical regions in the ventral neural system,
exaggerated activity within these regions, or failure
of top-down processes to downregulate the ventral
neural system. In other words, the ventral neural
system (amygdala) responding to threat is hyperactive, whereas the dorsal neural system (PFC and
58

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NEUROCIRCUITRY OF STRESS RESPONSE

Exposure to acute stress results in catecholamine
release peripherally through the sympatheticadreno-medullary system and an increase in the
stress hormone cortisol through the central hypothalamic-pituitary-adrenal (HPA) system [53]. The
hypothalamus stimulates the adrenal medulla to
release the catecholamines epinephrine and norepinephrine into the blood stream, which leads to
autonomic changes, such as increased heart rate,
blood pressure, respiratory rate, and skin conductance. These changes constitute a fight-or-flight
response that facilitates and directs attention and
arousal to the immediate threat while inhibiting
functions that are nonadaptive in the current situation, such as digestion and sexual behavior. Closely
following sympathetic-adreno-medullary activation
is activation of the HPA axis, which begins with the
secretion of corticotropin-releasing hormone from
the hypothalamus. Corticotropin-releasing hormone activates release of adrenocorticotropin hormone from the pituitary into the blood portal,
which then stimulates the adrenal cortex to secrete
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Can anxiety damage the brain? Mah et al.

glucocorticoids, or cortisol in humans. Circulating

glucocorticoids facilitates a cascade of physiological
changes, including increased metabolism, cardiovascular output, and glucogenesis, all of which
facilitate the fight-or-flight response. Glucocorticoids further play a key role in regulating the stress
response by providing inhibitory feedback at various
levels of the HPA axis, which terminates the stress
response once the stressor has subsided. All aforementioned events are orchestrated to allow the
individual to adapt to the demands of their changing environment, enabling a homeostatic balance of
physiological parameters within a dynamic environment, a process that has been termed allostasis [54].
Acute stress also increases release of the catecholamine dopamine in the PFC, a process that
is controlled by the amygdala [5557]. Dopamine
release occurs even with mild levels of stress in the
primate dlPFC [58]. Acute stress also increases norepinephrine levels in the PFC [59], through amygdalar activation of corticotrophin-release factor
receptors which, in turn, activate noradrenergic
neurons on the locus coeruleus [60]. In experimental studies with animals using dopamine or NE
agonists to elicit, and antagonists to block stressinduced PFC function, increased catecholamine
release in the PFC results in impaired function,
particularly in the domain of working memory
[6164]. Catecholamine levels are further increased
by glucocorticoid through blockage of transporters
on glia which normally remove extracellular catecholamines [65] and through its actions on the
hypothalamus and on suprahypothalamic regions
that contain glucocorticoid receptors, including the
PFC, amygdala, and hippocampus [66]. Glucocorticoid-sensitive hippocampal neurons provide negative feedback to the HPA axis to terminate the stress
response when it is no longer adaptive [67]. Regulation of HPA activity is also achieved through the
mPFC which plays a top-down role by modulating
hippocampal and amygdala activity via glucocorticoid negative feedback mechanisms [68].
Thus, the hippocampus and mPFC regions of the
dorsal neural system in fear neurocircuitry serve to
regulate emotions through functional connectivity
with the amygdala, and these regions additionally
regulate the stress response through glucocorticoidmediated feedback mechanisms.

IMPACT OF PATHOLOGICAL ANXIETY

AND CHRONIC STRESS EXPOSURE ON
THE BRAIN
Although adaptive in the short run, frequent, or
chronic activation of stress-sensitive systems can
lead to an eventual wear and tear of the

neuroendocrine system, which over time infringes

upon the function of other interconnected physiological systems, including immune, metabolic,
and cardiovascular systems. This breakdown in
the physiological milieu of the organism is referred
to as allostatic load and is associated with increased
risk of diseases, including cardiovascular disease,
diabetes, metabolic syndrome, and neuropsychiatric disorders [6971]. It has long been appreciated
that the experience of stress exacerbates mental illness, contributing to risk of depression [72], and
triggering the onset of disorders such as schizophrenia [73] or bipolar disorder [74] and development of PTSD [75]. It was recently reported that
women who experienced significant psychosocial
stress in middle age were at increased risk for
developing Alzheimers disease 20 years later
[76,77]. Anxiety symptoms also increase the risk
of Alzheimers disease in cognitively normal
elderly and in amnestic mild cognitive impairment
(aMCI), a prodrome of Alzheimers disease, by as
much as 2.5-fold [7881] (but see [8288]). Further,
anxiety in MCI is associated with Alzheimers
disease biomarkers including abnormal concentrations of Ab42 and t-tau in cerebrospinal fluid
[89]. Stress-level glucocorticoid administration in
animal models of Alzheimers disease results in
increased amyloid formation and tau accumulation
[90]. Although previous studies which included
depression as a covariate have found an inverse or
no association between anxiety and Alzheimers
disease [8284,88], we recently reported using data
from the Alzheimers disease neuroimaging initiative, that anxiety severity in aMCI, as measured by
the Neuropsychiatric Inventory, increased the rate
of conversion to Alzheimers disease, even after
controlling for depression and cognitive decline
[91 ]. The hazards ratio for anxiety was 1.33, indicating that risk of Alzheimers disease increased by
33, 78, and 135% for mild, moderate, and severe
anxiety, respectively. Anxiety severity in aMCI was
also associated with increased rate of atrophy within
the entorhinal cortex of the medial temporal lobe,
an early neuroimaging biomarker of Alzheimers
disease. To identify potential mechanisms to
account for the associations between stress and
development of affective and cognitive disorders,
we turn to the evidence on the impact of chronic
stress on the brain structure and function.
&

HIPPOCAMPAL DAMAGE
Enhanced receptor binding following chronic HPA
activation and subsequent increases in glucocorticoid secretion has been found to inflict detrimental
effects on the hippocampus in both animals and

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Geriatric psychiatry

humans [9294]. Chronic stress and excessive glucocorticoid exposure may compromise the integrity
of the hippocampus. This is evidenced by hippocampal atrophy, and decreased hippocampus
neurogenesis [95]. Damage or atrophy of the hippocampus is associated with a feed-forward impairment on the organisms ability to inhibit the HPA
axis once the stressor has subsided, leading to prolonged HPA activation and further neuronal damage
[96]. Notably, chronic stress is found to cause
decreases in brain-derived neurotrophic factor, a
brain chemical necessary for neurogenesis, which
in turn disrupts serotonin activity [97].
It has been suggested that deficits in hippocampus neurogenesis lead to affective and anxiety
disorders [98,99] and reinstatement of hippocampus
neurogenesis may be one mechanism of antidepressant action [100102]. Decreased neurogenesis in the hippocampus of rodents results in
cognitive deterioration, depressive-like symptoms,
and anxiety-like behaviors [103105]. A similar
phenomenon is observed in human studies, which
have reported hippocampal atrophy and HPA dysregulation in psychiatric disorders, including major
depressive disorder and posttraumatic stress disorder [106]. Chronic fluoxetine exposure led to
increased expression of myelination-related genes
in the hippocampus, which correlated negatively
with anxiety-like behavior in rats exposed to fluoxetine as adults or neonates [107]. In transgenic mice,
arrest of hippocampus neurogenesis impaired
associative learning, whereas also sensitizing mice
to the generalized fear and anxiety caused by fear
conditioning. Thus, adult hippocampus neurogenesis may enhance the ability to learn predictive
contingencies involving aversive events, whereas
attenuating the anxiety experienced during fear
conditioning [108 ]. This observation may account
for the co-occurrence of cognitive deficits in mood
and anxiety disorders or the depression and anxiety
often observed in dementia and individuals at risk
for dementia.
&

PREFRONTAL CORTEX DAMAGE

Chronic stress exposure in the rodent also causes
structural and functional degeneration of the PFC
[109]. Specifically, loss of dendrites and spines in the
pyramidal cells of the PFC occurs after sustained
stress exposure in the rat [110112] which correlated with impaired working memory [113]. Other
animal work suggests that chronic stress exposure is
circuit specific. In contrast to loss of dendrites in
the PFC, chronic stress increases dendritic growth
in the amygdala, which further accentuates the
imbalance in amygdalar versus PFC function (i.e.,
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enhanced bottom-up versus impaired top-down

processes) [114]. Further, PFC neurons are differentially affected by chronic stress. Although PFC
neurons that form cortico-cortical connections
show dendritic loss, orbital PFC neurons and the
subset of PFC neurons that activate the amygdala
do not atrophy during chronic stress [110,112].
In humans, decreased PFC gray matter volume correlates with exposure to adverse events [115].
Chronic stress is also associated with reduced
functional connectivity of the PFC [116] and
weakened PFC regulation of the amygdala [117].
Depressed adults followed over 3 years who had
remitted had less volume decline than nonremitted
patients in the hippocampus, anterior cingulate,
and the dorsomedial and dorsolateral regions of
the PFC [118]. Although the literature suggests
that stress-induced PFC degeneration may contribute to development of psychiatric disorders,
including depression and PTSD, whether this
mechanism also accounts for increase in dementia
risk is unknown.

EFFECT OF ANTIANXIETY TREATMENT ON

FEAR AND ANXIETY NEUROCIRCUITRY
It is important to note that stress-induced damage to
the hippocampus and PFC is not completely irreversible. In animals, desipramine, a selective norepinephrine blocker, can restore the cognitive
deficits induced by chronic unpredictable stress,
possibly by activating alpha 1-adrenergic receptors
in the mPFC [119]. The mood stabilizer lithium also
increases hippocampal neurogenesis [120], particularly under stress conditions [121]. Chronic lithium
treatment in bipolar patients increases HC volume
[122] and may stabilize cognitive decline in aMCI
[123]. Antidepressant treatment and physical
activity have both been found to increase hippocampal neurogenesis [124,125]. Consolidation of
amygdalar-PFC functional connectivity may be normalized following antidepressant treatment for
depression [126]. Prazosin, an alpha-adrenergic
antagonist, used to treat PTSD reduces flashbacks
and improves concentration suggesting PFC function may be improved (reviewed in [127 ]). A course
of treatment with the Selective serotonin reuptake
inhibitor citalopram for older adults with GAD lead
to increased functional connectivity between dlPFC
and vlPFC and parietal areas involved in attention
[128]. Cognitive-behavioral therapies for anxiety
disorders reduce amygdalar reactivity [129,130,
131 ], increase activity in PFC regions supporting
cognitive appraisal including dlPFC and dmPFC
[130,132] and enhance inverse functional connectivity between the amygdala and dmPFC [132].
&

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Can anxiety damage the brain? Mah et al.

Mindfulness training in GAD alters amygdala-PFC

connectivity [133] and even simple cognitive tutoring for math anxiety in children reduces amygdala
reactivity in addition to decreasing anxiety [134 ].
&

CONCLUSION
Chronic stress increases risk of major psychiatric
disorders such as depression, and more recently
has been linked with onset of dementia. Potential
mechanisms for these associations are suggested by
the experimental observations that stress enhances
amygdalar activity but leads to structural degeneration of the PFC and hippocampus, which in turn
leads to deficits in emotion regulation and cognitive
impairment. It is thus evident that pathological
anxiety/stress can damage the brain but this damage may be reversible using both pharmacological
and nonpharmacological interventions. Whether
antianxiety interventions can reduce risk of developing neuropsychiatric illness needs to be established with longitudinal studies.
Acknowledgements
None.
Financial support and sponsorship
L.M. holds grants from the Alzheimers Society of Canada and the Brain Canada MIRI grant. A.F. is supported
by the Mind and Life Institute.
Conflicts of interest
There are no conflicts of interest.

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