Genetics, Anatomy, and Biochemistry of Behavior



Genetics, Anatomy, and Biochemistry of Behavior





Like physical health, emotional health is a result of complex interactions among biological, social, and environmental influences. Disorders of health of either type result from aberrations or distortions in one or more of these influences at any time in a person’s life.

Theoretical difficulties exist when trying to separate biological from social and environmental factors in the etiology of psychiatric illness. Therefore, the term organic mental disorder, used in past years to describe behavioral symptoms with causes outside of the emotional range, now is rarely used. Furthermore, over the past few decades, the development of advanced techniques in neuroimaging and neurophysiology have shown that psychiatric function is influenced significantly by neuroanatomical and neurochemical factors. This chapter focuses on the contributions of these and other biological components to the expression of normal behavior and its disorders.


• GENETICS OF BEHAVIOR

The role of genetic influences on the development of physical conditions such as heart disease, diabetes, and cancer is well documented. Genetic influences are also important in the display of behavior and its disorders. Because behavioral disorders are expressed in and thus are confounded by the social setting, it is more difficult in behavioral than in physical disorders to isolate genetic from social and environmental etiologies. Research tools that can help separate and identify these factors include family risk, twin, and adoption studies.


Research studies

Family risk studies are used to distinguish between genetic and other risk factors in the etiology of disorders. For a behavioral disorder or trait, the frequency of its occurrence in the relatives of an affected individual, or proband, is compared with its frequency in the general population. If a genetic component is involved in its etiology, a disorder would be expected to have a higher concordance rate (i.e., if concordant, the disorder occurs in both relatives) in close relatives of people with the disorder than in more distant relatives or in the general population.

Twin studies also are used to identify genetic factors in disorders. These studies work on the assumption that, because monozygotic twins have the same genetic makeup, the likelihood of both twins having a disorder will be higher than that of dizygotic twins, who are only as similar genetically as siblings. Furthermore, this assumption should hold true whether the twins are raised in the same home or in separate adoptive homes. For many psychiatric and behavioral traits and disorders, anecdotal and documented findings in twin studies strongly support this hypothesis.



Psychiatric disorders

Research studies provide evidence that genetic factors are involved in the etiology of major psychiatric disorders such as schizophrenia and bipolar disorder (see Chapters 12 and 13). Although each of these disorders occurs in about 1% of the general population, persons with a close genetic relationship to patients with schizophrenia or bipolar disorder are more likely than those with more distant relationships to develop these disorders (Table 5-1). Recent studies suggest also that the volume of brain areas known to be involved in the symptoms of schizophrenia (e.g., gray matter in frontal lobes and language areas) is more similar in monozygotic than in dizygotic twin pairs (Thompson et al., 2001).

Although it has been difficult to link specific chromosomal markers with psychiatric illnesses, in some studies, schizophrenia has been associated with markers on chromosomes 1, 7, 8, and 22. Recently, markers for schizophrenia have also been identified on chromosome 6, a genetic variation in the dysbindin gene (Shi et al., 2009; Straub et al., 2002), chromosome 8, a genetic variant of the neureregulin 1 gene (Stefansson et al., 2002), as well as genes on chromosomes 13 and 21 which are associated with disturbed transmission of glutamate (Chumakov et al., 2002). It is of interest that markers on the long arm of chromosome 22 are also seen in velocardiofacial syndrome, a disorder that has been associated with an increased risk for schizophrenia (Table 5-2). Also, recent evidence suggests that a locus for increased risk for both bipolar disorder and major depressive disorder is present on chromosome 3, particularly 3p21.1 (Bipolar Disorder Genome Study Consortium, 2010).

Genetic factors also play a role in the etiology of personality characteristics. For example, personality features such as responsiveness to stimulation, fearfulness, activity level, and distractibility have a higher concordance rate in monozygotic twins than in dizygotic twins. Such factors also play a role in the etiology of personality disorders, a diagnosis that is made when an individual has significant difficulties in social or occupational functioning because of his or her personality characteristics (see Chapter 24).








table 5.1 RISK OF DEVELOPING SCHIZOPHRENIA AND BIPOLAR DISORDER IN RELATIVES OF PATIENTS























RELATIONSHIP TO PATIENT

APPROXIMATE RISK FOR SCHIZOPHRENIA (%)

APPROXIMATE RISK FOR BIPOLAR DISORDER (%)


No relationship (general population)

1

1


First-degree relative (sibling, dizygotic twin, child or parent) of a patient with the disorder

10

20


Child of two parents with the disorder

40

60


Monozygotic twin of a patient with the disorder

50

75


The personality disorders are organized in three groups or “clusters” by similarities in their presentations (see Table 24-4). When compared with the general population, relatives of patients in each of the clusters tend to have specific psychiatric problems. For example, patients with cluster A personality disorders (schizoid, schizotypal, and paranoid) are more likely to have relatives with psychotic disorders such as schizophrenia, whereas cluster B (histrionic, narcissistic, antisocial, and borderline) personality disorder patients are more likely to have relatives with major depressive and substance-abuse disorders. Cluster C (avoidant, obsessive-compulsive, and dependent) personality disorders have been associated with anxiety disorders in relatives (Bouchard, 2007).


Neuropsychiatric conditions

There is strong support for genetic factors in the etiology of a number of neuropsychiatric conditions. For example, family risk studies show that, although Alzheimer’s disease is present in only 10% of nonrelatives (see Chapter 18), 25% to 50% of close relatives of Alzheimer’s patients eventually develop the disease. There is also a higher concordance rate for Alzheimer’s in monozygotic than in dizygotic twins.

Several chromosomes have been linked to the development of Alzheimer’s disease. The most wellknown association is that of Alzheimer’s disease with chromosome 21 (amyloid precursor protein gene) since individuals with Down’s syndrome ( trisomy 21) who live beyond the age of 40 ultimately develop behavioral and neuroanatomical evidence of Alzheimer’s disease. Chromosomes 1 (presenilin 1 gene) and 14 (presenilin 2 gene) have also been linked to Alzheimer’s disease, particularly in the early onset type that is evident before the age of 60. Also, the presence on chromosome 19 of the apolipoprotein E2 (Apo E2) allele appears to decrease while the

presence of E4 allele (Apo E4) appears to increase the likelihood of developing Alzheimer’s disease, particularly in women (Bartrés-Faz et al., 2002). Specific chromosomal associations for other neuropsychiatric symptoms and disorders can be found in Table 5-2.








table 5.2 BEHAVIORAL MANIFESTATIONS OF CHROMOSOMAL NEUROPSYCHOLOGICAL DISORDERS















































































CHROMOSOME

DISORDER

BEHAVIORAL MANIFESTATIONS


1

Alzheimer’s disease

Depression, anxiety, early onset dementia (before age 60)


4

Huntington’s disease

Erratic behavior, psychiatric symptoms (e.g., depression), dementia


5

Sotos syndrome

Intellectual impairment, phobias, hyperphagia


7

Williams syndrome

Hypersociality, intellectual disability, behavioral problems, hypotonia


8

Cohen syndrome

Autistic behavior, intellectual disability


9

Dystonia musculorum deformans/torsion dystonia (DYT1 gene)


Tuberous sclerosis

Major depressive disorder, learning problems


Seizures, cognitive impairment, autistic behavior


11

Acute intermittent porphyria

Manic behavior, psychosis


12

Phenylketonuria

Attention deficit/hyperactivity disorder


13

Wilson’s disease

Depression, personality changes, thought disorders


14

Alzheimer’s disease

Depression, anxiety, early onset dementia


15

Chromosome 15 inversionduplication syndrome


Prader-Willi/Angelman syndrome

Seizures, autistic behavior, hypotonia


Intellectual disability, hypotonia, rage, stubborness, self-injury


16

Tuberous sclerosis

Seizures, cognitive impairment, autistic behavior


17

Neurofibromatosis-1


Charcot-Marie-Tooth disease


Smith-Magenis syndrome

Cognitive impairment, autistic behavior


Peripheral neuropathy, neuropathic pain


Intellectual disability, impaired expressive language, stereotyped behavior, clinging and dependency, seizures


18

Tourette’s disorder

Discontrol of language and movements May be mistaken for a behavior disorder


19

Alzheimer’s disease (site of the Apo E4 gene)

Depression, anxiety, late onset dementia (over 60 years of age)


21

Progressive myoclonic epilepsy Alzheimer’s disease (associated with Down’s syndrome)

Cognitive regression, aphasia, intellectual disability Early onset dementia


22

Metachromatic leukodystrophy


Neurofibromatosis-2


DiGeorge/velocardiofacial syndrome

Personality changes, psychosis, dementia


Hearing impairment


Schizophrenia, bipolar disorder, psychomotor retardation, language delay, ADHD, seizures


X

Fragile X syndrome


Kallman syndrome


Lesch-Nyhan syndrome


Rett syndrome

Autistic behavior


No sense of smell, lack of sex drive, depression, anxiety, fatigue, insomnia


Self-mutilation and other bizarre behavior, intellectual disability


Autistic behavior, hand-wringing, breathing abnormalities




case 5.1


THE PATIENT

A physician confirms that a 26-year-old woman is in her first trimester of pregnancy. During the discussion after the examination, the woman tells the doctor that her identical twin sister recently entered a psychiatric hospital. The patient explains that over the past few months her sister reported hearing the voice of God telling her that she was chosen for a special “mission.” The patient does not know her sister’s diagnosis but expresses concern that her own unborn child will develop the same illness.


COMMENT

Although more information must be gained to make a definitive diagnosis of the sister’s illness, the presence of auditory hallucinations (hearing voices) lasting over several months suggests schizophrenia (see Chapter 12). Alternatively, the patient’s sister may be showing the manic phase of bipolar disorder characterized by delusions of grandeur (being chosen for a special mission) (see Chapter 13). Although other factors are involved in their etiology, there is a significant genetic component to the development of both of these disorders. Because the patient has the same genetic makeup as her monozygotic twin sister, the risk to her own child is the same as it would be to her sister’s child or any first-degree relative.


MANAGEMENT

The patient should be advised that there are other nongenetic factors involved in the etiology of major psychiatric illness; however, if her sister has schizophrenia, her own child’s genetic risk for developing the illness is about 10%. Bipolar disorder has a higher concordance rate and her child’s genetic risk is about 20%. Counseling should be provided to help the patient understand the two disorders and their managements.

Other neuropsychiatric disorders with strong genetic components include Huntington’s disease and Tourette’s disorder (see Chapter 2). Offspring of one affected parent with Huntington’s disease, a fatal autosomal-dominant disorder associated with an abnormal gene on the short arm of chromosome 4, have a 50% chance of developing the disorder. Huntington’s disease (and Fragile X syndrome) also shows genetic anticipation, a phenomenon in which the disease has an earlier onset and more severe symptoms with each succeeding generation. A high percentage of patients with Tourette’s disorder have a family member who is also affected by the illness, and its concordance rate is higher in monozygotic than in dizygotic twins.


Substance-abuse disorders

Many people believe that substance-abuse disorders are caused by an individual’s weak self-control or poor choice of social peers. Although such social difficulties clearly exist among abusers, much recent evidence suggests that substance-abuse disorders such as alcoholism also have a genetic component. Evidence of genetic associations in alcoholism includes the following findings:



  • The concordance rate for alcoholism is about twice as high for monozygotic twins as it is for dizygotic twins.


  • Adopted children in adulthood tend to show the drinking patterns characteristic of their biological rather than their adoptive parents.


  • Alcoholism is about four times more prevalent in the biological children of alcoholics than of nonalcoholics.

Furthermore, the genetic component of alcoholism is related to both sex and age of onset; sons of alcoholics are at greater risk than their daughters, particularly if the sons begin to abuse alcohol before the age of 20.

Cocaine abuse is also associated with genetic factors. Early in this century, (McHugh et al., 2002), a polymorphism in the promoter region of the prodynorphin gene was shown to be associated with protection against cocaine abuse.


• BEHAVIORAL NEUROANATOMY

The human nervous system consists of the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS contains the brain (cerebral hemispheres, basal ganglia, and thalamus); brainstem (pons, medulla, and midbrain); and the spinal cord. The PNS consists of somatosensory (afferent), motor (efferent), and autonomic neurons. Although anatomically separate, the CNS and PNS function interactively.


The cerebral cortex

The area of the brain most closely associated with behavior is the cerebral cortex, although subcortical areas are also involved. The cortex can be segregated
functionally into sensory, motor, and association areas that act together to ultimately affect behavior.

The cortex also can be divided anatomically into frontal, temporal, parietal, and occipital lobes, as well as limbic lobes that contain the medial parts of the frontal, temporal, and parietal lobes. Behavioral alterations seen in people with brain lesions caused by accident, disease, or surgery illustrate the major neuropsychiatric functions of these areas and of other cortical regions (Table 5-3).








table 5.3 NEUROPSYCHIATRIC ANATOMY: FUNCTION AND DYSFUNCTION































































REGION/DIVISION

MAJOR FUNCTIONS

EFFECTS OF LESION ON BEHAVIOR


Frontal lobes



Dorsolateral convexity


  • Planning for future action (executive functions)


  • Decreased motivation, concentration, and attention



  • Disorientation



  • Mood disturbances


Orbitofrontal cortex


  • Control over biological drives



  • Part of the dopamine-driven “reward” circuit


  • Disinhibition and inappropriate behavior



  • Poor judgment



  • Lack of inhibition or remorse (“pseudo-psychopathic” behavior)


Medial cortex


  • Control of movement


  • Apathy



  • Decreased spontaneous movement (akinesia)



  • Gait disturbances



  • Incontinence


Temporal lobes






  • Memory



  • Learning



  • Emotion



  • Auditory processing


  • Impaired memory



  • Psychomotor seizures



  • Changes in aggressive behavior



  • Inability to understand language (i.e., Wernicke’s aphasia [left-side lesions])


Limbic lobes



Hippocampus


  • Memory storage


  • Poor new learning (anterograde amnesia)


Mammilary bodies


  • Memory processing



  • Memory of odors


  • Anterograde amnesia



  • Wernicke-Korsakoff syndrome


Amygdala


  • Coordination of emotional states, particularly anger and aggression, with somatic responses


  • Klüver-Bucy syndrome (decreased aggression, increased sexuality, hyperorality)



  • Decreased conditioned fear response



  • Inability to recognize facial and vocal expressions of anger in others


Parietal lobes






  • Somatic sensation and body image


  • Impaired intelligence



  • Impaired processing of visual-spatial information, (i.e., cannot copy a simple line drawing or a clock face correctly [right-sided lesions])



  • Gerstmann’s syndrome (i.e., cannot name fingers, write, tell left from right, or do simple math, and impaired processing of verbal information [left-sided lesions])


Occipital lobes






  • Vision


  • Visual hallucinations and illusions



  • Inability to identify camouflaged objects



  • Blindness



Frontal lobes. The frontal lobes have four major subdivisions. The first two, the motor strip and the supplemental motor area, are involved in movement; the third, Broca’s area, in language. The fourth subdivision is the prefrontal cortex.

Clinically occurring events, surgically imposed changes, and neuroimaging studies provide evidence for the behavioral functions of the prefrontal cortex. The famous case of Phineas Gage, a man who received a large prefrontal lobe lesion in an accident in the mid-19th century, first demonstrated the personality functions of the frontal lobes (Harlow, 1868). Although he had remarkably few obvious neurological problems, Gage demonstrated a significant personality change after his brain lesion healed. Friends reported “It is not Gage anymore.” A formerly nonaggressive person, Gage showed outbursts of anger after the accident. A respectful, energetic, persistent, and organized person before his accident, he began to show an inability to carry out plans and a lack of self-control and concern for others. In a similar way, some patients who have had bilateral prefrontal lobotomy, a surgical procedure used in the past to treat serious psychiatric illness, retain intellectual functioning but show uncharacteristic apathy and lack of “goal-directed” behavior after the surgery.

Perseveration, engaging in repeated unnecessary behavior and thought, disinhibition, and sudden outbursts of temper, as well as reinstatement of the infantile sucking and rooting reflexes (frontal release signs) are seen in patients with prefrontal lobe damage; this is now known as prefrontal lobe syndrome. Interestingly, schizophrenia and obsessive-compulsive disorder (OCD), both of which are characterized by personality and affective changes, are associated with decreased bilateral prefrontal cortical activity as measured by functional magnetic resonance imaging (fMRI) and positron emission tomography (Baxter, 1999) (see Chapter 6).



case 5.2


THE PATIENT

After a mild stroke, a hospitalized 64-year-old former firefighter begins to show uncharacteristic impulsivity and mood changes. The nurses report that when the patient was found walking down the hospital hallway naked, he explained that he was “just trying to cool off.” The patient’s wife believes that his strange behavior is because of posttraumatic stress disorder as a result of a life-threatening fire he witnessed the previous month. The physician believes instead that the patient’s behavior fits the diagnosis of “personality change due to a general medical condition” and is a direct result of the injury to his brain caused by the stroke. To further evaluate this patient, the doctor orders a computed tomography scan, an MRI, and a series of neurological tests.


COMMENT

It can be difficult to gauge whether a change in behavior after a neurological insult is because of damage to the brain. This case is problematic because of the temporal juxtaposition of an intense psychosocial stressor (the fire) with the physical insult to this patient’s brain caused by a stroke. Tests used to distinguish neurological from emotional symptoms include the Mental Status Examination, the Folstein Mini-Mental State Examination, and neuropsychiatric tests such as the Bender Visual Motor Gestalt Test (see Chapter 6).

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Jun 16, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Genetics, Anatomy, and Biochemistry of Behavior

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