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1 The Neurobiology of Mental Illness 2 Neurobiology 3 4 The Neurobiology of Mental Illness Untangling Cause and Effect The study of the neurobiology of an illness looks at genetic, physical & environmental aspects of behavioral disease Studying these three aspects of a disorder gets us much closer to the real causes of these disorders Nature v Nurture is dead Mental Disease is a complex interaction of both genes and environment Schizophrenia Mood disorders Anxiety disorders Substance Use Dementia Autism ADHD Personality disorders OCD Aggression Eating Disorders Menstrual Cycle disorders 5 6 A Word About Genes 7 Genetic Differences in Identical Twins 8 A Word About Environment 9 John B. Watson All medical and behavioral disorders have a genetic basis Sensitivity to environmental factors is genetic Having a gene is not the same as expressing it Stress often “turns on” a unexpressed gene The genes you have when you are born are not always the genes that you have when you die Your genes change with time Even the genes of identical twins will diverge across time As they age, twins grow more genetically distinct Epigenetics is the study of environmental impact on genes There are no genes without an environment A harsh environment will overcome a good gene A severe genetic abnormality will undercut the best environment Most of us are in the middle People with dopamine disorders have a harder time in even the best of environments A child psychologist who thought that physical affection was bad for children A generation of children were denied affection because of his teaching This may have led to many dysfunctional adults still alive today 10 The Germ Theory of Infection 11 12 How To Think About Genes 13 Genes Are Like Computer Programs We have forgotten about the effects of infectious disease 800,000 in the US died in the 1918 flu epidemic 9,000 people died every day for 3 months 20 - 50 million died world-wide in less than one year Genes are encoded instructions on how to build a specific person/animal/plant Some routines play in development, but many are unexpressed until specific triggers cause them to activate So, you can be born with a gene and not express it until later in life Or you can engage in behaviors that change your DNA Some are programmed to come up when you boot your computer, but others are in there for you to call up when you need them You can begin to “express” a gene anytime in your life You can begin to “express” a gene anytime in your life Bipolar disorder often develops after a stressful event It’s still a genetic disorder 14 DNA Genes & Chromosomes 15 Nuclear Disasters 16 Copy Number Repeat Diseases 17 Are Mental Disorders Increasing? 18 Cause of Autism 19 20 21 Genetic Anticipation 22 23 Schizophrenia & Bipolar Disorder Will Genetic Research Influence the Treatment of Mental Disorders? 24 The Neurobiology of Schizophrenia 25 A Long Time Ago 26 What Is Schizophrenia? 27 Schizophrenia Chromosomes are comprised of long strings of DNA wrapped around histones Genes are segments of DNA plus the histones Histones can be altered by environmental factors We are learning that there have been many more Russian nuclear disasters than previously known The cumulative radiation released into the world’s atmosphere is much greater than experts believed Many psychiatric disorders are due to erroneous numbers of genes copied into the genome Fragile X syndrome Huntington’s Spinocerebellar Ataxia Lower infant mortality rate 6 million released from state hospitals in the 1950’s Resulting in 12 million children by 1980 Resulting in 24 million children by 2000 People marry later in life increasing the likelihood of germ cell mutations Eric Kandel Psychiatrist - Nobel Laureate “Genetic anticipation” refers to the deterioration of genetic material as it is copied down the generations For some mental illnesses the age of onset decreases and the symptoms gets more severe in each new generation Parents of bipolar children may be unfairly blamed for worsening disease actually due to genetic anticipation Genetic data will provide information for the development of new drugs Will help remove stigma Decrease erroneous thinking r.e. causality Increase personal responsibility for disease management It will not effect therapies that rely on the interpersonal relationships The Physics of Thought Schizophrenia was thought to be a “mental” disease because no structural differences were seen in the brains of schizophrenics Things have changed. We can now easily see the structural and chemical changes that exist in the brain tissue of schizophrenics SZ is not a single disease but a collection of genetic disorders that alter cognition and perception SZ has a range of severity and multiple causes Subtypes? Variations? Best thought of as a “spectrum” of disease Common features are disordered perception, thought and judgment An error in the ability to process “reality” in the form of sensory input Synesthesia is another type of error in processing An inability to distinguish internally generated data from external experience Appears to require a defect in two areas in the brain Thalamus (sensory integration) (positive symptoms?) Pre-frontal cortex (judgment) (negative symptoms?) Appears to require a defect in two areas in the brain Thalamus (sensory integration) (positive symptoms?) Pre-frontal cortex (judgment) (negative symptoms?) 28 Thalamic & Frontal Damage Damage to the thalamus causes alterations to perceptions Alterations in frontal lobe function makes patients believe the perceptions are real rather than internally generated phenomena 29 30 31 Crossroads In The Brain Schizophrenia Symptoms of Schizophrenia Hallucinations Delusions Decreased focused attention Disorganized thought Cognitive impairment Flattened affect Withdrawal Paranoia Poverty of speech Disorganized speech Social anxiety Dysexecutive syndrome 32 Variants of Schizophrenia 33 Problems Defining Schizophrenia 34 35 The Many Symptoms of Schizophrenia Decreased Focused Attention 36 37 Attention Deficits 38 39 Positive & Negative symptom clusters Positive = delusions, hallucinations, paranoia (respond to medication) Negative = apathy, social disfunction, withdrawal, flat affect (don’t respond) The classical subtypes used in the DSM-IV, paranoid, disorganized, catatonic, undifferentiated, residual have been removed from the DSM 5 Catatonic Described in the past - not seen now - may have been due to brain injury Schizoaffective Mix of perceptual distortion and mood disorder Schizophrenia research suffers from an inability to develop a stable set of diagnostic criteria There are many places to look for disease Chemical Structural Behavioral Genetic Developmental Congenital We do not understand why schizophrenia presents so differently in different patients Brain activity occurs in two modes, a background trickle and brief bursts Schizophrenics have a hard time separating background information from the important bursts They tend to find importance in trivial details Nicotine helps them to focus on what’s real Many mental disorders have attentional disruption as a core symptom Nicotine helps the brain focus on important stimuli and ignore things that are unimportant Nicotine activates areas in the brain that filter stimulation “I’ll be surprised if there is not a co-therapy [for schizophrenia] that takes advantage of nicotine systems in less than a decade” Physical Brain Differences Ventricular enlargement Decreased volume Small thalamus Decreased volume Small thalamus Gliosis Hypofrontality Cell migration defects Alterations in dopamine serotonin & glutamate 40 Ventricular Enlargement 41 Hypofrontality 42 43 44 Hypofrontality In Identical Twins New Evidence For Frontal Lobe Dysfunction Decreased Hippocampal Volume 45 Early Cortical Degeneration 46 Neural Networks Damaged In Schizophrenia This condition worsens with time as the brain continues to lose volume Left side greater than the right Alters memory formation Increases confabulation Temporal Lobe Schizophrenia is a Dementia Brain areas do not function separately from each other Most mental illnesses occur on an “axis” or loop of several brain areas that are linked by neurons that produce the same chemicals 47 Emil Kraeplin & Alois Alzheimer Pioneering neurologists who thought both Alzheimer’s and schizophrenia were degenerative Both considered these diseases as dementias 48 Cellular Migration Defects 49 50 Too Many Connections Overactivity & Underactivity 51 Schizophrenia Is ... 52 53 Wouldn’t anyone be crazy if they saw or heard things that weren’t there? Synesthesia 54 55 Synesthesia Synesthesia 56 57 Causes of Synesthesia Scans of Crossed Pathways 58 Feeling Music Cellular confusion Too many cells in some areas Too few in others Glial cells that guide the patterning of cells are thought to be abnormal in schizophrenia Some parts of the brain are overactive (temporal) Some areas are underactive(frontal) Resulting in a mix of perceptual and behavioral symptoms An early defect in the thalamus that alters physical perception Neurotransmitters that send signals are effected Additional left-frontal damage prevents insight into perceptual errors A rare genetic disorder that causes the brain to mix sensory perceptions Synesthetes see music, taste sound, hear color etc. The perceptual changes are stable for each person across their lifetime The most common form is color-number The next most common form is sound-color The cause of synesthesia is a gene that causes two or more areas of the brain to respond to a single sensation May alter the chemical balance between two sensory systems May alter the chemical balance between two sensory systems 58 59 Feeling Music Testing for Synesthesia 60 Synesthesia 61 Color Is In The Brain 62 63 64 Understanding Schizophrenia 65 Cognitive Therapy 66 Etiology of Schizophrenia 67 Genetic Defects 68 69 The Genain Quadruplets 70 39 Year Followup 71 Is Schizophrenia Genetic? 72 Polygenetic Inheritance 73 Schizophrenia Is Not Simply Inherited 74 A Developmental Disorder 75 Etiology of Schizophrenia Color Makes The Numbers Easy To See Each synesthete is a little different and sees and hears a different set of sensations Synesthetes were shown black and white cartoons that contained numbers They reported seeing the numbers in color The colors corresponded to their personal “palate” Like synesthesia schizophrenia alters the brain’s ability to perceive the environment The symptoms interfere with their ability to work and socialize Unlike synesthesia patients have no insight into their perceptions Synethetics have no damage to the frontal lobes Strengthening the Frontal Lobe The Genetic Defect Hypothesis The Neurodevelopmental Hypothesis Excitotoxcicity-Neurodegenerative Hypothesis SZ clearly runs in families There is a tenfold increase in risk in 1st degree relatives There is little other evidence for direct genetic transmission Every major genetic linkage study has failed Symptoms of SZ do not even follow the Mendelian rules for inheritance Identical quadruplets All had schizophrenia but differed significantly in presentation Risk was 1.5 billion to 1 Both parents were severely mentally ill Cause of their disease still debated Schizophrenia is not fully penetrant 50% of identical twins do not get the disease Symptoms of schizophrenia can be causes by other means Schizophrenia is not independent of environment No genetic study has ever been completely successful Probably not just one disease Science, August 2008 “Thus, the tight one-to-one relationship that exists between disease gene and phenotype does not apply to schizophrenia.” Events that occur during critical periods of fetal growth can negatively impact brain development In the 2nd trimester, neuronal migrations take place that form critical cortical connections Many studies show that women exposed to trauma or pathogens at this time have a higher risk of having a child with schizophrenia As many as 13/15 in some studies Many studies show that women exposed to trauma or pathogens at this time have a higher risk of having a child with schizophrenia As many as 13/15 in some studies 75 Etiology of Schizophrenia 76 Defects in Cortex Development 77 Factor Analysis of Schizophrenia 78 Haldol In The Brain 79 The DSM 5 80 Summary 81 The Neurobiology of Anxiety 82 What Is Anxiety? 83 Stress & Survival 84 Anxiety & Survival 85 86 Pain & Survival Update 87 Anxiety Disorders 88 Not Within Normal Limits Damage to cortical sub-plate in the 2nd trimester of pregnancy Some of the risk factors are: Viruses Malnutrition Severe psychological stress Obstetrical complications Probably anything that interferes with growth and neuronal development Cortex is formed as neurons migrate from the cortical plate through the intermediate zone Excess neurons are produced and must die back As much as 50% of initial neural growth Defects in neuronal migration and cell death account for perturbed connections in the brain Positive Symptoms (temporal lobe) Delusions Hallucinations Negative Symptoms (frontal lobe) Social withdrawal Disorganized thought (frontal lobe) Thalamus and Frontal Cortex The overall definition of schizophrenia has not changed greatly in DSM 5 A patient must have at least 2 characteristic symptoms for at least one month These include delusions, hallucinations, disorganized speech, abnormal psychomotor activity There must be social/occupational dysfunction over a six-month duration Schizophrenia appears to be a disorder of both genetic and environmental cause Interference with cell death sends neurons to the wrong places Sometimes triggered by infection, starvation or injury during pregnancy A simultaneous loss of pre-frontal and thalamic function occurs interfering with sensory integration and judgment about what is real and unreal Paranoid personality disorder may be the frontal lobe/judgment deficit without the sensory errors Fear and Loathing in the Brain Anxiety is the brain & body’s natural response to threat Anxiety is necessary for survival Thus, a complex and sensitive system has evolved to alert us to danger This system is deeply ingrained When this natural system for self-preservation goes awry excess anxiety and panic may result This system predates the development of cognition and so is based mostly in the midbrain and brainstem Much of the brain exists to cause stress and anxiety Historically these important emotions helped us survive Without negative emotions humans do not live long Anxiety and depression can be characterized as survival-related communication from the brain People who lack fear and anxiety often do not live long Gabby Gingras In the DSM-IV diagnosed only when responses were judged to be out of proportion to the situation 88 89 Not Within Normal Limits Cultural Factors 90 Expression of Emotion 91 92 93 The Neurobiology of Fear Anxious Dogs Role of the Amygdala 94 Role of the Amygdala 95 96 It is generally believed that most, perhaps all, specific fears are learned through experience. For example, monkeys in the wild are afraid of snakes but monkeys raised in labs are indifferent to them. Primal Fear 97 Amygdala 98 Role of the Hippocampus 99 Role of the Prefrontal Cortex Appropriate response to a stressor varies by culture American’s are very ambivalent regarding emotional reaction We praise “human emotion” but do not want to deal with it in our families and ourselves We medicate feelings that are normal expressions of emotions Change Across Time The amygdala processes fear, anxiety and rage Specific fears are not innate, but are learned through experience Lab monkeys are not afraid of snakes The brain-stem response to fear is innate & includes sweaty palms, racing heart, shaking In other words, people can be afraid of many different things, but how the emotion of fear is experienced is always the same Our old, primitive brain responses for survival can be triggered by modern events For a neutral stimulus to begin produce the behavioral response of fear and anxiety, it is only necessary for that stimulus to activate the amygdala The amygdala signals the rest of the brain to produce the response of fear Individuals with an “overactive” amygdala will be more likely to respond to many things with fear Electrical stimulation of the amygdala will also cause a classic fear response Temporal lobe epilepsy paranoia The amygdala sends info to the hippocampus which is instrumental in assigning meaning to the stimulus “Content conditioning” Chronic stress has been found to be especially damaging to the hippocampus Anxiety disorders may occur when a pre-stressed hippocampus too readily assigns a stimulus as something to fear Preparation to respond to threat requires integration between brains areas that assess and interpret a stimulus (amygdala & hippocampus) and brain areas involved in judging how to respond (frontal lobe and cingulate cortex) Multiple studies have found PTSD and panic patients to have pre-existing prefrontal disfunction 100 101 102 The Basic Fear Response Pathway of Anxiety Neurochemistry in Anxiety 103 The Expression of Fear is Universal in Humans 3 Major Neurotransmitters Noradrenalin Dopamine Serotonin 3 Minor chemical messengers GABA (benzodiazepines) Opioid peptides Cholecystokinin (pain killers) This was established by Darwin and was reported in his first book, The Expression of Emotion in Man and Animals Prior to this, emotions were not thought to be the same across cultures This was established by Darwin and was reported in his first book, The Expression of Emotion in Man and Animals Prior to this, emotions were not thought to be the same across cultures 104 Bodily Response in Fear 105 The Eyes Express Fear 106 Amygdaloid Overactivity 107 Amygdaloid Damage 108 William’s Syndrome 108 108 108 109 Neurochemistry of Fear 110 Etiology of Anxiety 111 The DSM Anxiety Disorders 112 Prevalence of Anxiety Disorders 113 The Pattern of Normal Anxiety Pounding heart Dry mouth Fidgeting Apprehensive expectation Upset stomach Increased respiration Scanning and vigilance Jumpy, quick startle Evacuation of bladder Evacuation of bowels More than any other part of the body, fear can be seen in the eyes Adrenaline causes a widening of the eyes to gather more light and allow better judgment Anxious subjects show extra activity in the amygdala Mild damage to the amygdala can cause increased aggression Severe damage causes decreased perception of danger or anger and blunts the behavioral response to threat Williams syndrome is characterized by medical problems, including cardiovascular disease and learning disabilities. These occur side by side with striking verbal abilities, highly social personalities and an affinity for music. They require supervision because they do not fear anything Nor-adrenaline Corticotropin Releasing Hormone Neurosteroids Arginine Vasopressin Neuropeptide Y Galanin GABA Dopamine Serotonin Benzodiazepines Opioid peptides Genetic studies show some genetic predisposition for excessive fear but little evidence for a specific disease A nonspecific vulnerability to anxiety appears to be inherited, but environment and experience may be large factors in which type of anxiety is developed PTSD, Panic Disorder and General Anxiety are more similar than different Panic Disorder with/without Agoraphobia Specific Phobia Social Phobia Obsessive-Compulsive Disorder Post-traumatic Stress Disorder Generalized Anxiety Disorder 30% of Americans will experience a diagnosable anxiety disorder some time in their lives Panic affects 9-10 % of the population Social phobia in 13% of the population Simple phobias in 10-11% of the population Generalized anxiety disorder in 5% OCD found in 1-2% of the population OCD found in 1-2% of the population 113 The Pattern of Normal Anxiety 114 Reconsolidation 115 Extinction 116 Extinction 117 Risk Factors for Anxiety Disorder 118 119 Initial stressor Consolidation Reconsolidation Extinction Whereby a prior experience can undergoes another round of placement into memory It is the rule, rather than the exception that memories are reactivated by cues associated with the original trauma or experience Reconsolidation can cause a memory to strengthen, change or weaken Medications can interfere with reconsolidation (Benzos-Beta blockers) Can they be used to lessen anxiety without loss of other forms of learning? Extinction occurs when an event recurs without a negative consequence After a while the fear lessens Immersion therapy uses extinction to reduce the brain’s response to a specific fear Immersion works well with classic phobias When immersion therapy fails it may be because the stated trigger for fear is incorrect Women who claim to be afraid of flying are often actually fearful of depriving their children of care Immersion therapy using airplane interiors will fail in these cases Damaged/poorly functioning amygdala Damaged/poorly functioning hippocampus Damaged/poorly functioning prefrontal cortex 120 Nosology of Anxiety Disorders The Neuroses 121 The Neuroses 122 DSM-3 123 Diagnostic Difficulties 124 Newer Data on Anxiety 125 126 The Cycle of Panic Disorder Panic Disorder Early Psychiatry referred to anxiety as “anxiety neurosis” The neuroses were defense mechanisms created in childhood to adapt to imperfect parenting Most people were thought to have some form of neurosis Caused by poor parenting Psychotherapy treats neuroses by providing increased insight reducing the need for immature (fearful) responses to stress Measures of neuroticism are excellent predictors for the development of anxiety disorders and PTSD later in life Neuroses were removed as a diagnostic category in 1980 The anxiety disorders were put in their place The older categories were based more on Freudian concepts then empirical research Few medications were available and the focus was on therapy Unlike schizophrenia our current classification of anxiety disorders is not based on modern knowledge of neurophysiology or even treatment response This makes the relationship between DSM anxiety disorders and a specific neuro-pathway difficult to establish As research develops we may change our vocabulary about anxiety disorders New data suggests that Panic Disorder is a genetically based alteration in the brain’s perception of threat A standardized symptom profile for Generalized Anxiety Disorder has yet to be established Criteria for PTSD have been expanded in DSM 5 to include seeing stressful events on television Social phobia and PTSD may be more of a pre-existing personality disorder triggered by an environmental stressor Prevalence is 4% of population 126 Panic Disorder 127 Social Anxiety 128 129 Generalized Anxiety Disorder 130 Post-traumatic Stress Syndrome Prevalence is 4% of population Genetic predisposition - 11p 50% of patients have a chronic relapsing-remitting pattern No known biomarkers Still, easier to diagnose as symptoms are more specific Highest response to medications SSRIs and imipramine first line MAOIs are second line agents Response to cognitive behavior therapy almost as high as medication treatment Best recovery rate of all anxieties Individuals with social anxiety have over-active amygdalas that fire when the person is stressed This can be in situations that ordinary people do not find stressful Groups of people, public speaking etc. 5% prevalence rate More females than males Characterized by chronic persistent anxiety 30% concordance in identical twins Genetic markers found in serotonin and norepinephrine systems Most people exposed to severe stress never show symptoms of PTSD Individuals with PTSD show evidence of hypofrontality on PET scans They were functioning within their limits until a major stressor required more frontal coping ability than they were capable of maintaining Subjects were no longer able to use the frontal lobe to modulate their amygdala 131 PTSD 132 133 134 135 136 137 Genetic Variations Genes Interact With Environment Treatments For Anxiety 138 History of Treatment for Anxiety 139 Trans-cortical Magnetic Stimulation 140 Benzodiazepines for Anxiety PTSD is the anxiety disorder that is hardest to treat Perhaps because the brain is responding to a real threat Individuals with smaller hippocampi are at higher risk of developing PTSD if they experience a trauma Anxiety Can Be Conquered Treatment Cognitive-behavior therapies work by improving frontal judgment to reassign new meaning to previously feared stimuli i.e. increasing frontal inhibition of amygdala response Drug therapies work by using chemicals to reverse or quiet overactive brain areas New drugs may be developed that can be specific to the amygdala or hippocampus TMS may also be used to increase frontal lobe function and inhibit anxiety Prior to 1950, psychotherapy was the only option In the 1950s benzodiazepines were discovered In the late 1980s the SSRIs introduced Buspar came shortly thereafter In the 1990s, anticonvulsants and SNRIs were developed Transcortical magnetic stimulation is in development This treatment uses an electromagnet to stimulate the brain in specific areas It is being used to treat depression, OCD and anxiety Benzodiazepines (Valium, Ativan) were the first medications found to be effective in treating symptoms of anxiety They work by reducing activity in the sub-cortex and frontal lobes This reduction in activity can also treat seizures Disadvantages include memory and cognitive loss in the elderly They work by reducing activity in the sub-cortex and frontal lobes This reduction in activity can also treat seizures Disadvantages include memory and cognitive loss in the elderly Also muscle weakness and disinhibition in everyone 141 Benzo-diazapines 142 Tricyclic Antidepressants 143 Anti-convulsants for Treatment of Anxiety 144 SNRI Librium (1960) Valium (1963) Ativan Klonopin Serax Halcion Xanax A large class of chemical agents that effect the serotonin system Proven effective in treating anxiety but …. Many have significant side-effects and are no longer recommended Valproic Acid Gabapentin Lamictal Topiramate Serotonin Norepinephrine Reuptake Inhibitor Venlafaxin (Effexor) 145 RIMAs 146 147 The Tricyclic Antidepressants Common Side-effects of TCAs Reversible inhibitors of monoamine A Similar in action to MAOIs but reversible and do not require a special diet Not available in the USA Found in tobacco! Dry-mouth Constipation Urinary retention Confusion Blurred vision Orthostatic hypotension Sedation Cardiac arrhythmia's Muscle weakness Increased glaucoma 148 Attitudes About Psychotherapy 149 Anxiety Spectrum Disorder 150 151 Hoarding "We are in a society that is enamored of high tech. So people think that psychotherapy is just handholding —that it cannot actually have a serious impact on a person or his brain. This is one of the reasons it is so important to get scientific results that lend credibility to psychotherapy as a real treatment" Glen Gabbard, MD Menninger Clinic A proposed method of regarding the wide breadth of symptoms associated with the term anxiety It recognizes that anxiety can be a normal response to expected life stressors Anxiety would exist on a continuum rather then be present or absent In the past, hoarding behavior has been classed as a variant of OCD Recent research using fMRI has revealed that hoarders brains resemble bereavement and pathological grief In the past, hoarding behavior has been classed as a variant of OCD Recent research using fMRI has revealed that hoarders brains resemble bereavement and pathological grief hoarders appear to be suffering from chronic loss Hoarding is now in the DSM 5 152 DSM 5 153 154 A Look Into The Future Beta Blockers & PTSD Classification of anxiety disorders did not change dramatically in DSM 5 Generalized anxiety disorder has been renamed generalized anxiety and worry disorder Time frames have been lessened from 6 months to 3 months for symptom duration Criteria for PTSD has been softened and will increase diagnosis DSM 5 allows me to witness to disaster or even reactions to learning about a disaster at a later date to qualify for a diagnosis of PTSD Taking propranolol directly after a frightening event prevented the development of fear but did not appear create amnesia for the event 155 156 157 Future Treatments for Anxiety? Transcranial Magnetic Stimulation Summary 158 Summary 159 160 Questions Major References Mental Illness is the most common cause of disability in the US Mental illness is not mental The brain comes in three parts Each has its own type of memory & processing using different chemicals and pathways in the brain Mental health requires smooth integration of all three areas Damage to parts of the limbic system create misperceptions of reality Emotional Illness appears to be caused by a dysfunction in the limbic system coupled with a dysfunction in the frontal lobe areas for reasoning and judgment These two defects create disturbed perception along with the inability to gain insight Treatments can focus on altering the chemical messengers in the limbic system or increasing frontal function through insight Both types of treatments are equally valid Both result in physical changes in the brain 1. The Neurobiology of Mental Illness Dennis Charney, Eric Nestler 2. The Frontal Lobes & Neuropsychiatric Illness Stephen Salloway, Paul Malloy, James Duffy 3. Neuropsychiatry & Behavioral Neuroscience Jeffery Cummings, Michael Mega 4. Neuroscience (2nd Edition) Mark Bear, Barry Connors, Michael Paradiso