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September 10, 2013 | Major Depressive Disorder, Depression, Neuropsychiatry, Special Reports
By Georg Northoff, MD, PhD

Underlying mechanisms of increased self-focus Linked Articles

Introduction: Treatment
Increased self-focus is closely related to its sibling, decreased environment focus: the more the focus is on content Along the Life Cycle
related to oneself, the less the focus is directed toward environmental content not related to oneself. As long as Depression-Related
perceptions, cognitions, and attention are abnormally directed toward oneself, the patient is unable to detach from her Disparities Among Older,
own contents and view the world in an objective (rather than subjective) way. Increased self-focus goes hand in hand Low-Acculturated US
with predominantly negative emotions rather than positive emotions. Latinos

Opportunities and
The increased self-focus may also be accompanied by an increased focus on one’s body. The patient experiences and Challenges in Treating
perceives her body in a most hypersensitive way. This, in turn, can lead to various somatic symptoms.7,17,18 Adolescents and Young
Adults With Major
Functional imaging can be used to investigate that relationship between self and negative emotions. We used functional Depressive Disorder
imaging to gauge the degree of self-relatedness of subjects. In accordance with clinical symptoms, depressed patients Special Issues in
attributed increased degrees of self-relatedness to especially negative emotional pictures: the more negative the Menopause and Major
emotions, the higher the degree of self-relatedness attributed to it. This, in contrast, was not the case in healthy cohorts, Depressive Disorder
who related increased degrees of self-relatedness to increased degrees of positivity in the emotional pictures.14,19 Psychopathology and
Pathophysiology of
The imaging data show altered neural activity in the anterior midline regions, such as the anterior cingulate cortex and Depression
the ventromedial and dorsomedial prefrontal cortex, during the self-relatedness when subjects were shown pictures with Augmentation Strategies
emotional content (Figure).14,19,20 Emotion-inducing pictures that have a high degree of personal relevance to the in MDD Therapy
viewer (ie, self-relatedness) stimulate activity changes in the midline regions. In contrast, emotional pictures that remain
rather irrelevant to the person do not induce a strong activity in the midline region. This suggests that the increased
resting state activity in these regions is directly related to increased self-focus. This is further underlined by findings in
healthy subjects in whom neural overlap can be observed in the anterior midline regions.21-23

Figure

(Figure): Cortical midline structures and the self

(A) Distinction between self and non-self: cortical midline structures and domain independence. The figure on the left depicts all the imaging studies on the self as plotted in their
obtained location on one brain. This includes self-referential stimuli in various domains or functions, such as memory, social, and spatial, as indicated by the colors. On the right, 3
different coordinates (x, y, z) are shown that determine the direction (medial-lateral, inferior-superior) of the location in the brain. All studies locate in the midline regions of the

brain (left image) as seen in the x-coordinate that describes the medial-lateral location (right image). (B) Cortical midline structures: anatomical definition.
brain (left image) as seen in the x-coordinate that describes the medial-lateral location (right image). (B) Cortical midline structures: anatomical definition.

MOPFC, medial orbital prefrontal cortex; PACC, perigenual anterior cingulate cortex; VMPFC, ventromedial prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; SACC,
supragenual anterior cingulate cortex; PCC, posterior cingulate cortex; MPC, medial parietal cortex; RSC, retrosplenial cortex.

What about the increased body focus? Interceptive stimuli are processed in the insula, a region on the outer surface where interoceptive and
exteroceptive stimuli from body and environment converge and are integrated. We studied depressed patients during awareness of their body (heart
beat counting) and during exteroceptive awareness (tone presentation).3,4 The Body Perception Questionnaire (BPQ) was used to measure awareness
of the body. Patients with depression showed significantly higher values in the BPQ, indicating higher degrees of body awareness. This is compatible
with the assumption of an increased body focus.

Neural activity

Patients with depression show increased resting state activity in the insula. This, in turn, leads to decreased neural differentiation between
interoceptive and exteroceptive stimuli in the insula. Exteroceptive stimuli are processed more or less in the same way as interoceptive stimuli.
Because of the lack of interoceptive-exteroceptive differentiation, exteroceptive stimuli are experienced in terms of the body rather than as
environmental stimuli that are distinct from the body. Awareness is shifted toward one’s body, which can explain at least in part the increased body
focus.

If exteroceptive stimuli are less strongly processed in the brain, interoceptive stimuli are more strongly represented in the neural activity of the brain.
Such a shift in the balance between interoceptive and exteroceptive stimulus processing may be manifested in an analogous shift in the contents of
our awareness and attention. The body becomes the primary content of our awareness, and attention toward environmental content is reduced.5,24
Ultimately, this results in an increased focus on the body rather than the environment.

Therapeutic implications

A study of patients in the acute state of depression and patients with depression in remission found that the activity changes in the insula reversed and
normalized during remission.3 This means that the abnormal insula activity may be considered a predictive marker of therapeutic effects and thus of
possible remission. However, additional studies are needed to support these results.

What is the biochemical level that is relevant for pharmacological treatment? The neural activity in the brain is generated on the basis of neural
excitation and inhibition. There are 2 biochemical substances that generate neural excitation and inhibition. Glutamate is the main transmitter that
mediates neural excitation, while γ-aminobutyric acid (GABA) in​duces neural inhibition that results in an excitation-inhibition balance. GABA, induced
by specific stimuli, is also related to neural activity in particular regions.

Wiebking and colleagues 5,24 have shown that the neurotransmitter GABA plays a central role in both the anterior cingulate cortex and the insula: GABA
mediates exteroceptive awareness in the pregenual anterior cingulate cortex; it also mediates the neural activity during specifically interoceptive
awareness in the insula. This is compatible with the initial therapeutic effects of benzodiazepines such as lorazepam, which provide some initial relief
of depression symptoms (although they do not improve the mood itself).

Conclusion

Novel and more specific psychotherapeutic approaches that target increased self-focus and body focus and decreased environment focus can be
developed as we gain more insights into the pathophysiological basis in the subcortical and cortical midline regions and their exact underlying neural
mechanisms. Psychotherapeutic approaches that train the patient to shift his awareness from the internal to the external might also improve patient
outcomes. In the future, imaging studies may be used to see how these interventions affect neural activity in the insula and the midline regions.

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DISCLOSURES

Dr Northoff is Research Unit Director: Mind, Brain Imaging, and Neuroethics; and Michael Smith Chair in Neurosciences and Mental Health at the
University of Ottawa Institute of Mental Health Research at the Royal Ottawa Mental Health Centre. He reports no conflicts of interest concerning the
subject matter of this article.

REFERENCES

References

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3. Wiebking C, Bauer A, de Greck M, et al. Decrease in insula subregions predicts therapeutic recovery in depression. Psychol Med. In press.

4. Wiebking C, Bauer A, de Greck M, et al. Abnormal body perception and neural activity in the insula in depression: an fMRI study of the depressed
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framework for a system disorder. Neurosci Biobehav Rev. 2011;35:1929-1945.

8. Raichle ME, MacLeod AM, Snyder AZ, et al. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:676-682.

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