This document discusses the neurobiology of major depressive disorder (MDD) by examining the key brain regions, neurotransmitter systems, and circuits involved. It begins by outlining the major dopamine, norepinephrine, and serotonin projections in the brain. It then discusses how depressed mood and apathy may relate to inefficient information processing in specific brain regions regulated by these neurotransmitters. The document goes on to summarize the areas of the brain implicated in MDD, including the prefrontal cortex, amygdala, hippocampus, and others. It also outlines cortico-cortical circuits and basal ganglia neurocircuitry that may play a role in the pathology of psychiatric disorders like MDD. Finally, it discusses recent directions in understanding M

2. Prof. Hani Hamed Dessoki, M.D.Psychiatry
Acting Dean, Faculty of Nursing
Prof. Psychiatry
Founder of Psychiatry Depart., Beni Suef University
Supervisor of Psychiatry Depart., El-Fayoum University
Treasurer of Egyptian Psychiatric Association
2020
From Circuits to Symptomatology

3. Agenda
 Introduction
 Neurotransmitters
 Circuits
 Anatomical sites
 Take home Message
 Recent direction

7. Depressed mood is believed to be
linked to inefficient information
processing in the amygdala (A) and
the ventromedial prefrontal cortex
(VMPFC), both of which are innervated
by serotonergic (A), noradrenergic (B),
and dopaminergic (C) projections from
brainstem nuclei.

8. Apathy is believed to be related
to inefficient information
processing (depicted here as
blue or hypoactive) diffusely
through the prefrontal cortex
(PFC) as well as in
hypothalamic centers (Hy)
and the nucleus accumbens
(NA).
These functions within the prefrontal cortex and hypothalamus are thought to be
regulated in part by noradrenergic neurons that project there (A), while within
prefrontal cortex, hypothalamus, and nucleus accumbens these functions are
also thought to be regulated by dopaminergic projections (B).

10.  Dopamine also plays a role in fatigue, with
deficient dopaminergic functioning in the PFC
related to mental fatigue and deficient
dopaminergic functioning in the striatum (S),
nucleus accumbens (NA), hypothalamus
(Hy), and SC related to physica fatigue.

11. Different neurotransmitters
may affect different symptoms
in depression
Energy
Alertness
Noradrenaline
Serotonin
Obsessions
and compulsions
Anxiety
Irritability
Mood
Emotion
Appetite
Sex
Loss of
interest
Dopamine
Attention
Motivation
Pleasure
Stahl S. Essential Psychopharmacology. 2000; Nutt DJ, et al. J Psychopharmacol 2007; 21: 461471.
Nutt DJ. J Clin Psychiatry 2008; 69 Suppl E1: 47; Shelton AJ & Tomarken RC. Psychiatr Serv 2000; 52: 1469–1478.
GABA
Inhibit release/
activity of each other
Influence
release/ activity
of each other
Influence
release/activity
of each other
Glutamate
Increases NA
release within
locus coeruleus
Influence
release/ activity
of each other
Serotonin decreases
glutamatergic activity
within PFC

12. Areas of the Brain Implicated in MDD
Charney DS, et al. Neurobiology of Mental Illness. 2nd ed. 2004.
Prefrontal Cortex (PFC)
• Involved in the “executive
functions,” such as
working memory,
decision-making,
planning, and judgment
Amygdala
• Performs a
primary role in
processing and
memory of
emotional
reactions
Hippocampus
• Important for the
forming, and
perhaps storage, of
associative and
episodic memories
Thalamus
Nucleus Accumbens
Anterior Cingulate Cortex (ACC)
• Plays a role in rational cognitive
functions such as reward
anticipation, decision-making,
empathy, and emotion
• Integrates emotional stimuli and
attentional functions
Cerebellum
Insular Cortex
• Processes convergent
information to
produce an
emotionally relevant
context for sensory
experience
Somatosensory Cortex

13. ‫اعرف‬‫انت‬‫بكتب‬‫ايه‬‫وبتخاطب‬‫مين‬‫وجرعة‬‫كام‬

18. Key brain regions

21. Major dopamine projections
 Dopaminergic neurotransmission is associated with movement, pleasure and
reward, cognition, psychosis, and other functions.
 In addition, there are direct projections from other sites to the thalamus, creating
the "thalamic dopamine system," which may be involved in arousal and sleep.

22. Major norepinephrine projections
Regulate mood, arousal, cognition, and other functions.
Descending noradrenergic projections extend down the spinal
cord and regulate pain pathways.

23. Major serotonin projections
 Regulate mood, anxiety, sleep, and other functions.
 Descending serotonergic projections extend down the brainstem
and through the spinal cord; they may regulate pain.

24.  Nor epinephrine regulation of serotonin
 Regulates serotonin by acting as a brake on serotonin release at alpha 2
receptors on axon terminals and as an accelerator of serotonin release at
alpha 1 receptors at the somatodendritic area 5HT2A

26. Major acetylcholine projections via
brainstem.
 These projections may regulate arousal,
cognition, memory, and other functions.

27. Histamine is predominantly involved in sleep and wakefulness.

28. Cortico-cortical interactions
 Information from different brain regions is
processed and communicated via neuronal
interconnections that form functional loops, or
circuits.
 One type of functional loop is a cortex-to-cortex
circuit, or corticocortical interaction (A).
 Corticocortical interactions can also be mediated
by input from neurotransmitter nodes (B).


31. Key cortico-cortical circuits
 Several important prefrontal corticocortical
circuits are shown here.
 The anterior cingulate cortex (ACC) has
corticocortical interactions with the dorsolateral
prefrontal cortex (DLPFC) and the orbital frontal
cortex (OFC). The OFC, in turn, has
corticocortical interactions with the
hippocampus.
 The DLPFC has only sparse direct connections
with the amygdala and hippocampus.

33. Hypothetical CSTC Loop for Executive Functions
DLPFC - Striatum - Thalamus —> DLPFC

34. Hypothetical CSTC Loop for Attention

43. Lesions to OFC region
- depression,
- mood instability and
- anxiety
• Has central role in self-regulation of emotion and
social behavior
• Elevated metabolic activity or perfusion of the OFC in
young to middle aged
Unipolar acutely depressed subjects
• Potentially elevated OFC activity and tissue loss is
consistent with the
operation of an excitotoxic process

51.  These neurotransmitter projections can be either inhibitory or excitatory,
depending on the neurotransmitter and the receptor involved; however, their
actions may be more subtle than those of GABA and glutamate.

53. Pyramidal neuronal
function and receptor stimulation
 Receptors can be both
under- and overstimulated.
 Optimal tuning of signal-to-
noise ratios.
 This means that in some
cases, neurotransmission
needs to be increased, but
in other cases it may need
to be decreased.

54. Molecular sites for regulating monoamines,
 Two molecular sites important for
regulating monoamines and thus for
maintaining efficiency of cortical circuits
are
(1) the enzymes that break down
monoamines and
(2)monoamine transporters.
 Examples of enzymes include
monoamine oxidase A (MAO-A) and
catechol-O-methyl transferase (COMT).
 Examples of monoamine transporters
include the serotonin transporter (SERT).

55. Role of basal ganglia neurocircuitry
in the pathology of psychiatric
disorders?

56. The basal ganglia is a
distributed group of subcortical
nuclei comprised mainly of the
striatum (including the caudate
nucleus and putamen of the
dorsal striatum and the nucleus
accumbens [NAc] of the ventral
striatum), substantia nigra
(SN), globus pallidus (GP),
ventral pallidum (VP),
subthalamic nucleus (STN), and
ventral tegmental area (VTA).

57. Five common psychiatric disorders:
obsessive–compulsive disorder,
substance‐related and addiction disorders, major
depressive disorder, generalized anxiety
disorder, and schizophrenia.
Finally, we present a model based upon the findings
of these studies that highlights the striatum as a
particularly attractive target for restoring normal
function to basal ganglia neurocircuits altered within
psychiatric disorder patients.

60. Endocrine systems
• HPA Activity
• Thyroid Axis
Activity
• Growth Hormone
• Prolactin

64. Recent Directions

65. diagnosis
trials and errors
effective treatment
TODAY….
TOMORROW….
tailor made

66. Future of Behavioral Health has
Arrived
 Patients with depression and anxiety are frustrated with drug
treatments because of poor response (up to 5 trials).
 Also, some of these medications increase anxiety, resistance to
treatment, insomnia, and sexual dysfunction.
 Sometimes they may quit medications.
 It is better to choose psychotropic medications based on the
individual genetic characteristics, metabolizing pathways leading to
better medication tolerance.
 This give the patient the confidence to continue treatment.
 Test can done by a simple cheek swab (Assure Rx- GeneSightRx).

68. Cells Show Signs of Faster Aging After
Depression
Study found structures called telomeres were shorter in people with the condition
By Brenda Goodman
HealthDay Reporter
TUESDAY, Nov. 12 (HealthDay News) -- The cells of people who have had depression
may age more quickly, a new study suggests.
Dutch researchers compared cell structures called telomeres in more than 2,400 people
with and without depression.
Like the plastic tips at the ends of shoelaces, telomeres cap the ends of chromosomes to
protect the cell's DNA from damage. Telomeres get a bit shorter each time a cell
divides, so they are useful markers for aging.
The researchers found that the telomeres of people who had ever been depressed were
significantly shorter -- about 83 to 84 base pairs of DNA shorter, on average -- than
those of people who had never suffered from depression.
The results remained even after researchers accounted for a host of lifestyle factors that
can also damage DNA, such as heavy drinking and cigarette smoking.
Since people naturally lose about 14 to 20 base pairs of DNA in the telomeres each year,
the researchers said the difference represents about four to six years of advanced
aging.