Evolutionary Development If you examine the brain in an evolutionary perspective, this can help to understand the interlinks between form and function. The brain can be divided anatomically and functionally into three basic components.

Reptilian Brain Corresponds to the brainstem Consists of the medulla, pons, midbrain and basal ganglia Not only responsible for vegetative functions but also for many volitional behaviours directed towards individual preservation and propagation such as feeding, drinking and sexual aggression.

Paleomammalian Brain The primitive cortex of the limbic lobe Subserves primitive (but distinctly mammalian behaviours) such as hoarding and parental care of offspring.

The limbic system Amygdala :response to fear Prefrontal cortex : integrates this emotion with conscious sources of information and plans our physiological and behavioral responses to the situation. Hippocampus : consolidation of conscious memories and cognitive navigation Cingulate gyrus : error detection, determining the focus of our attention, the personal sense of urgency and social interactions

Basal Ganglia and Limbic System

Hippocampal Formation & Amygdala Hippocampal Formation Dentate gyrus + the hippocampus proper + Subiculum Memory, spatial navigation and attention Amygdala Via hypothalamus activates the ANS Activation of Neurotransmitters Emotional Learning – Conditioning Memory modulation Kluver Bucy Syndrome – Docility: diminished fear responses, dietary changes, Hyperorality, Hypersexuality, Visual Agnosia Hypermetamorphosis: irrresistable impulse to notice and react to everything, memory loss

Function of the Limbic System Affective Functions Playful moods Emotions and feelings, Like wrath, fright, passion, Love, hate, joy and sadness Self preservation

Prefrontal cortex Dorsolateral cortex(DLC) :Attention, planning, decision making, inhibition, and initiation of goal- directed behavior, working memory The orbitofrontal cortex (OFC) :inhibit the emotional and autonomic reactivity of subcortical structures such as the amygdala.

Fear Neurocircuitry

Fear Extinction Circuitry

Frontal Lobe Dysfunction The Primary motor cortex Contra lateral motor control The medial frontal cortex Arousal and motivation – Abulic (Apathy & inattention The orbital frontal cortex Modulate Behaiour – Labile, euphoric, facetious, vulgar The left postero-inferior frontal cortex (Broca’s) Language – expressive Aphasia The dorsolateral frontal cortex Working memory & dysexecutive syndrome

Disorders that affect the forebrain RegionDisorder Cerebral cortexdepression, Huntington's disease, mania Cerebrumepilepsy, stroke frontal lobeAlzheimer's disease, depression, mania,schizophrenia parietal lobe Alzheimer's diseasea temporal lobeAlzheimer's disease, depression, mania Limbic system mania amygdala depression hippocampusAlzheimer's disease, mania

Serotonin Pathways

Serotonin and Depression

Serotonin transmission – Caudal raphe nuclei and Rostal raphe nuclei is reduced in depression Increasing the levels of serotonin in these pathways, by reducing serotonin reuptake = treatment

Serotonin and Schizophrenia

Serotonin in Schizophrenia Dorsal raphe nuclei – Substantia Nigra Rostal raphe nuclei – cerebral cortex, limbic regions and basal ganglia The up-regulation of Serotonin pathways leads to the hypofunction dopamine pathways = negative symptoms The serotonergic nuclei in the brainstem that give rise to descending serotonergic axons remains unaffected in schizophrenia

Dopamine pathways

Depression may have systemic health consequences 1.Hypothalamus stimulates the pituitary gland to release excessive ACTH, continuously driving the adrenal gland 3. Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias 2. The adrenal gland releases excessive amounts of catecholamines and cortisol 4. Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension 5. Cortisol antagonizes insulin and contributes to dyslipidemia, type 2 diabetes, and obesity; increases in cortisol also suppress the immune system ACTH Adapted from: Musselman DL, et al. Arch Gen Psychiatry. 1998;55(7): Musselman DL, et al. Arch Gen Psychiatry. 1998;55(7):

Normal Stress Response: HPA Axis ACTH released from pituitary Glucocorticoids released from adrenal cortex Glucocorticoids provide negative feedback to hypothalamus CRF released from hypothalamus Stressor

Stress sensitization and Brain Atrophy Hippocampal Atrophy Disinhibition of HPA Axis by Hippocampus Prolonged Glucocorticoid Release Prolonged Stress

Cellular atrophy after stress Rat hippocampal neurone before (A) and after (B) 3-week repeated stress

Stress Decrease in neurogenesis Cellular atrophy Decrease in hippocampal volume Frodl et al. Am J Psych. 2002; McKittrick et al. Synapse. 2000; Duman R. CNS Spectrum, Structural changes in brain in depression

Neuroplasticity The brain's natural ability to form new connections in order to compensate for injury or changes in one's environment.

Evidence of Hippocampal Atrophy and Loss in Patients With MDD 1.Bremner JD, et al. Am J Psychiatry. 2000;157(1): Sheline YI, et al. J Neurosci. 1999;19(12): Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93(9): Sheline YI, et al. Am J Psychiatry. 2003;160(8): Images courtesy of JD Bremner. Compared to controls, patients with depression had smaller hippocampal volumes (n=16) 1 Decreased hippocampal volume may be related to the duration of depression 2-4

Correlation Between Hippocampal Volume and Duration of Untreated Depression Sheline YI, et al. Am J Psychiatry. 2003;160(8): Reprinted with permission from APA. 38 Female Outpatients With Recurrent Depression in Remission Days of Untreated Depression Total Hippocampal Volume (mm 3 ) R 2 =.28 p=.0006 N= There was a significant inverse relationship between total hippocampal volume and the length of time depression went untreated

Beyond the Synapse: Brain-derived Neurotrophic Factor (BDNF), Depression, and Antidepressants Neurogenesis (the birth of new neurons) continues postnatally and into adulthood – BDNF is associated with production of new neurons and their growth and development 1 – Data suggest that neurogenesis occurs in the hippocampus 2 The hippocampi appear to have important functions related to both mood and memory – Data from depressed patients have shown reduced hippocampal volume 3 BDNF may influence regulation of mood 4 BDNF is downregulated in MDD and increased with successful antidepressant treatment 4,5 Both serotonin (5-HT) and norepinephrine (NE) are believed to play roles in the modulation of BDNF 1,5 1. Duman RS, et al. Arch Gen Psychiatry. 1997;54(7): Gould E, et al. Biol Psychiatry. 2000;48(8): Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93(9): Shimizu E, et al. Biol Psychiatry. 2003;54(1): Maletic V, et al. Int J Clin Pract. 2007;61(12): Image courtesy of Society for Neuroscience.

The Role of BDNF in Neuronal Changes in stress Duman RS, et al. Biol Psychiatry. 2000;48(8): Sapolsky RM. Arch Gen Psychiatry. 2000;57(10); Maletic V, et al. Int J Clin Pract. 2007;61(12): Musselman DL, et al. Arch Gen Psychiatry. 1998;55(7): Stress Increased Secretion of Glucocorticoids Increased Activity of HPA Axis Normal Survival and Growth HPA = hypothalamic pituitary adrenal Production of Inflammatory Cytokines and Catecholamines Decreased Dendritic Branching Atrophy/Death of Neurons BDNF

The monoamine hypothesis of gene action: The impact of stress on BDNF Adapted from: Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.