Doctor, I am depressed, and sad. What do I have doctor ? Please tell me.

You have depression.

Gee – isn’t that what I just told you?

Can’t you give me any added value?

?!?

Doctor, my stomach hurts. What do I have, doctor ? Please tell me. You have gastritis.

Doctor, my stomach hurts. What do I have, doctor ? Please tell me. You have gastritis. Doctor, I am depressed, and sad. What do I have, doctor? Please tell me. You have depression.

Doctor, my stomach hurts. What do I have, doctor? Please tell me. You have gastritis. Doctor, I am depressed, and sad. What do I have, doctor ? Please tell me. You have depression. Place in the body What happened to it It is infected How to treat it Antibiotics

Doctor, my stomach hurts. What do I have, doctor? Please tell me You have gastritis Doctor, I am depressed, and sad. What do I have, doctor ? Please tell me. You have depression. ? ? ? Place in the body What happened to it? It is infected How to treat it Antibiotics

Gastroenteritis Gastroenterologist Mitral Valve Prolapse Cardiologist Urologist Depression Psychiatrist ? Glomerulonephritis

Gastroenteritis Gastroenterologist Mitral Valve Prolapse Cardiologist Urologist Depression Psychiatrist ? Glomerulonephritis

Medicine = Etiological Diagnosis Psychiatry = Descriptive Diagnosis SPACE

PsychosisMoodAnxiety Psychosis due to injuries etc. Negative symptoms Deficiency Positive symptoms delirium Schizophrenia Depression Mania Reactive Secondary Endogenous Major Mixed anxiety and depression Psychosis Depression Mania Psychosis Schizoaffective disorder Generalized Phobia Personality disorders Learning disability OCD PTSD Eating disorders

…. “we are at the epicycle stage of psychiatry where astronomy was before Copernicus and biology before Darwin”….

Neuroscience Phenomenology Enormous gap The clinician sees a patient not neuronal networks or neurotransmitters

Why we failed ?

Proposed RDoC

Clinical Brain Profiling CBP

Clinical Brain Profiling CBP Explanatory power

Clinical Brain Profiling CBP Translation matrix

Neuroscience Phenomenology Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN

Neuroscience Phenomenology Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN Psychosis Disconnection Syndrome

Neuroscience Phenomenology Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN

Neuroscience Phenomenology Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN

Neuroscience Phenomenology Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN Clinical Brain Profiling CBP Based on Literature Publications Based on Neural network simulations Based on 20 years of theoretical work

Sign 1 Sign 2 Sign 3 Sign 4 Sign 5 Sign 6 Sign N Symptom 1 Symptom 2 Symptom 3 Symptom 4 Symptom 5 Symptom N Cs Disconnection Ci Over connection De-optimization Hyper-optimization Constrain frustration Disturbed DMN Clinical Brain Profiling CBP Predicted disturbance CF(b) = 2 DMN =5 Cs =10 Ci =3 Hbu =7 Htd =1 D = 13 O =0 CF =5

Cardiac Insufficiency Brain Insufficiency Diagnose Algorithm of Disturbance Correct with Pacemaker Algorithm of Disturbance Correct with Brain Pacemaker

Cardiac Insufficiency Brain Insufficiency Diagnose Algorithm of Disturbance Correct with Pacemaker Algorithm of Disturbance Correct with Brain Pacemaker Phenomenology Brain disturbance

General Neuroscientific consideration

Emergent Properties One neuron has no awareness or feelings but many organized neurons do. The whole is more than the sum of its parts (10 7 )

Emergent Properties One neuron has no awareness or feelings but many organized neurons do. The whole is more than the sum of its parts (10 7 ) Marcel Mesulam From sensation to cognition Mesulam 1998

Emergent Properties One neuron has no awareness or feelings but many organized neurons do. The whole is more than the sum of its parts (10 7 ) Marcel Mesulam From sensation to cognition Mesulam 1998 Bernard Baars 1980s

Emergent Properties One neuron has no awareness or feelings but many organized neurons do. The whole is more than the sum of its parts (10 7 ) Marcel Mesulam From sensation to cognition Mesulam 1998 Bernard Baars 1980s Stanislav Dehene 2006

10 10 (10 7 ) Marcel Mesulam From sensation to cognition Mesulam 1998 Stanislav Dehene 2006 Giulio Tononi Unitary Undividable 2-3s Taps into large repertoire Statistical combinations One of billion others thus dramatically reduces uncertainty Information = reduction of uncertainty (entropy) thus Can be quantified with Information measurements Ф = ( info in whole ) measures complexes Bernard Baars 1980s Emergent Properties One neuron has no awareness or feelings but many organized neurons do. The whole is more than the sum of its parts.

To make as perfect or effective as possible Optimization To find the best compromise among several often conflicting requirements

To make as perfect or effective as possible Optimization To find the best compromise among several often conflicting requirements Small World Network

Clustering Coefficient = Measure of density of connections between nearest neighbors Path length = inversely related to global efficacy of parallel information transfer Small-worldness = high clustering small path length comparable to random graph Hierarchy = Hubs with many long distance connections and few local connections Rent exponent = topo-physical embedment in physical space of the network, scaling relationships Mean connection distance = Euclidean distance between centers in stereotactic space Assortativity = measures the preference of a node to connect to other nodes of similar degree

Specific Neuroscientific consideration

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) EGO

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 EGO Experience dependent plasticity

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 EGO=Default mode network EGO Experience dependent plasticity Internal Representations

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Loosening associations

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Loosening associations Psychosis

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Loosening associations Psychosis

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Loosening associations Perseverations Psychosis

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Loosening associations Perseverations PsychosisNegative, (restriction)

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Negative symptoms Loosening associations Perseverations PsychosisNegative, (restriction)

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Negative symptoms Loosening associations Perseverations PsychosisNegative, (restriction) Negative (volition)

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Negative symptoms Loosening associations Perseverations PsychosisNegative, (restriction) Negative (volition)

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Negative symptoms Loosening associations Perseverations Delusions PsychosisNegative, (restriction) Negative (volition)

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Theodore Meynert ( ) Donald Hebb 1948 Carl Rogers Otto Kernberg Hinz Kohut EGO=Default mode network EGO Experience dependent plasticity Internal Representations Object relations psychology Personality & Personality Disorders Karl Friston Free Energy Giulio Tononi Matching complexity De-optimization Optimization Depression Elevated mood Mania Multiple constraint frustration Anxiety Herbert Simon 1962 Marcel Mesulam Negative symptoms Loosening associations Perseverations Delusions PsychosisNegative, (restriction) Negative (volition) Delusional

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Delusions Hallucinations History of delusions depressed Complains of depressed mood History of depression Complains of Confused thoughts Signs Symptoms History Translation of signs and symptoms to presumed brain disturbances Testable predictions ??? Validation

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Delusions Hallucinations History of delusions depressed Complains of depressed mood History of depression Complains of Confused thoughts Signs Symptoms History Is it as good as scales ? Is it good as consensual current descriptive ?

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Wolf RC, Sambataro F, Vasic N, Schmid M, Thomann PA, Bienentreu SD, Wolf ND. Aberrant connectivity of resting- state networks in borderline personality disorder. J Psychiatry Neurosci Mar 1;36(2):100150

Theodore Meynert ( ) Donald Hebb 1948 EGO=Default mode network EGO Experience dependent plasticity Internal Representations [DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Wolf RC, Sambataro F, Vasic N, Schmid M, Thomann PA, Bienentreu SD, Wolf ND. Aberrant connectivity of resting- state networks in borderline personality disorder. J Psychiatry Neurosci Mar 1;36(2):100150

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Wolf RC, Sambataro F, Vasic N, Schmid M, Thomann PA, Bienentreu SD, Wolf ND. Aberrant connectivity of resting- state networks in borderline personality disorder. J Psychiatry Neurosci Mar 1;36(2): Congdon E, Mumford JA, Cohen JR, Galvan A, Aron AR, Xue G, Miller E, Poldrack RA. Engagement of large-scale networks is related to individual differences in inhibitory control. Neuroimage Nov 1;53(2): Epub 2010 Jun 30 Monk CS, Nelson EE, Woldehawariat G, Montgomery LA, Zarahn E, McClure EB, Guyer AE, Leibenluft E, Charney DS, Ernst M, Pine DS. Experience-dependent plasticity for attention to threat: Behavioral and neurophysiological evidence in humans. Biol Psychiatry Oct 15;56(8): Volkow ND, Tomasi D, Wang GJ, Fowler JS, Telang F, Goldstein RZ, Alia-Klein N, Woicik P, Wong C, Logan J, Millard J, Alexoff D. Positive emotionality is associated with baseline metabolism in orbitofrontal cortex and in regions of the default network. Mol Psychiatry Apr 12

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE Yu Q, Sui J, Rachakonda S, He H, Pearlson G, Calhoun VD. Altered small-world brain networks in temporal lobe in patients with schizophrenia performing an auditory oddball task. Front Syst Neurosci Feb 8;5:7.

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE Yu Q, Sui J, Rachakonda S, He H, Pearlson G, Calhoun VD. Altered small-world brain networks in temporal lobe in patients with schizophrenia performing an auditory oddball task. Front Syst Neurosci Feb 8;5:7. Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A. Dysconnectivity in schizophrenia: Where are we now? Neurosci Biobehav Rev Apr;35(5): Epub 2010 Nov 27.Review Jones MW. Errant ensembles: dysfunctional neuronal network dynamics in schizophrenia. Biochem Soc Trans Apr;38(2): Review Bassett DS, Bullmore E, Verchinski BA, Mattay VS, Weinberger DR, Meyer- Lindenberg A. Hierarchical organization of human cortical networks in health and schizophrenia. J Neurosci Sep 10;28(37): Bodnar M, Harvey PO, Malla AK, Joober R, Lepage M. The parahippocampal gyrus as a neural marker of early remission in first- episode psychosis: a voxel-based morphometry study. Clin Schizophr Relat Psychoses Jan;4(4): Guye M, Bettus G, Bartolomei F, Cozzone PJ. Theoretical analysis of structural and functional connectivity MRI in normal and pathological brain networks. MAGMA Dec;23(5- 6): Epub 2010 Mar 27.Graph

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Nissen C, Holz J, Blechert J, Feige B, Riemann D, Voderholzer U, Normann C. Learning as a model for neural plasticity in major depression. Biol Psychiatry Sep 15;68(6):

[DDMN] Disturbance to the default mode network [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DMCO] Disturbance to Multiple constrain organization [ibDMCO] Input bound Disturbance to Multiple constrain organization [DD] Disconnection Dynamics [OD] Over-connection Dynamics [TDS] Top down shift [BUI] Bottom-up Insufficiency Signs Symptoms History Nissen C, Holz J, Blechert J, Feige B, Riemann D, Voderholzer U, Normann C. Learning as a model for neural plasticity in major depression. Biol Psychiatry Sep 15;68(6): J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE J Neurosci.J Neurosci Nov 24;30(47): Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. van den Heuvel MPvan den Heuvel MP, Mandl RC, Stam CJ, Kahn RS, Hulshoff Pol HE our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regionsMandl RCStam CJKahn RSHulshoff Pol HE Yu Q, Sui J, Rachakonda S, He H, Pearlson G, Calhoun VD. Altered small-world brain networks in temporal lobe in patients with schizophrenia performing an auditory oddball task. Front Syst Neurosci Feb 8;5:7. Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A. Dysconnectivity in schizophrenia: Where are we now? Neurosci Biobehav Rev Apr;35(5): Epub 2010 Nov 27.Review Jones MW. Errant ensembles: dysfunctional neuronal network dynamics in schizophrenia. Biochem Soc Trans Apr;38(2): Review Bassett DS, Bullmore E, Verchinski BA, Mattay VS, Weinberger DR, Meyer- Lindenberg A. Hierarchical organization of human cortical networks in health and schizophrenia. J Neurosci Sep 10;28(37): Bodnar M, Harvey PO, Malla AK, Joober R, Lepage M. The parahippocampal gyrus as a neural marker of early remission in first- episode psychosis: a voxel-based morphometry study. Clin Schizophr Relat Psychoses Jan;4(4): Guye M, Bettus G, Bartolomei F, Cozzone PJ. Theoretical analysis of structural and functional connectivity MRI in normal and pathological brain networks. MAGMA Dec;23(5- 6): Epub 2010 Mar 27.Graph Wolf RC, Sambataro F, Vasic N, Schmid M, Thomann PA, Bienentreu SD, Wolf ND. Aberrant connectivity of resting- state networks in borderline personality disorder. J Psychiatry Neurosci Mar 1;36(2): Congdon E, Mumford JA, Cohen JR, Galvan A, Aron AR, Xue G, Miller E, Poldrack RA. Engagement of large-scale networks is related to individual differences in inhibitory control. Neuroimage Nov 1;53(2): Epub 2010 Jun 30 Monk CS, Nelson EE, Woldehawariat G, Montgomery LA, Zarahn E, McClure EB, Guyer AE, Leibenluft E, Charney DS, Ernst M, Pine DS. Experience-dependent plasticity for attention to threat: Behavioral and neurophysiological evidence in humans. Biol Psychiatry Oct 15;56(8): Volkow ND, Tomasi D, Wang GJ, Fowler JS, Telang F, Goldstein RZ, Alia-Klein N, Woicik P, Wong C, Logan J, Millard J, Alexoff D. Positive emotionality is associated with baseline metabolism in orbitofrontal cortex and in regions of the default network. Mol Psychiatry Apr 12

Central Executive Network Default Mode Network Salience Network [DD] Disconnection Dynamics [OD] Over-connection Dynamics [BUI] Bottom-up Insufficiency [TDS] Top down shift [DMDd] Disturbance to Matching dynamics Deoptimization type [DMDo] Disturbance to Matching dynamics Optimization type [DDMN] Disturbance to the default mode network

NeuroAnalysis Validation How to detect, diagnose & monitorNetwork disturbancesClinical phenomena Age-related changes resting-state functional connectivity MRI (rs-fcMRI) (Van Dijk KR et al 2010) Age related Matching complexity, Free energy estimations, Entropy measurements integrated information theory Disturbances to development of default mode network Personality disorders Short-term over time Dynamics of Matching complexity, Free energy estimations, Entropy measurements integrated information theory Disturbances to Optimization dynamics Mood & Anxiety Small world network analysis for hub composition, Estimating hierarchy, k-shell decomposition percolation theory and fractal geometry Hierarchal (top-down bottom-up) disorders Schizophrenia delusions and abolition Correlations, Synchrony, Granger causality, Mutual information, Dimension estimation, Bayesian statistics Dynamic Causal Modeling, Independent components analysis Neural complexity (Correlation matrix), overall Small world network analysis Connectivity imbalances Disconnection over- connection Schizophrenia Disorganization deficiency

Cardiac Insufficiency Brain Insufficiency Diagnose Algorithm of Disturbance Correct with Pacemaker Algorithm of Disturbance Correct with Brain Pacemaker Phenomenology Brain disturbance

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