First a look at the Mind:

An organ weighing about 3-4 pounds containing about 100 billion neurons which is ironically also the number of stars in the Milky Way. The brain cells are indeed different. Different neurons have different shapes but if their molecular differences are accounted for, each neurons might be classified as having its own structure. The brain definitely is not made up of interchangeable parts. But neurons that work similarly are bunched together. For example, neurons of visual cortex are devoted to a local circuitry busy converting specific signals. One similarity between neurons is that they all conduct along axons i the form of brief electrical impulses called action potentials beating wings of Cajal's butterflies. Action potential measuring about 100 millivolts i amplitude and one milliseconds in duration result from the movement of positively charged sodium ions across the surface membrane from the outside fluid where the sodium concentration is 10 times higher. Inside of neurons is negatively charged with respect to the outside. Physical or chemical stimuli change the permeability of neuron membrane, allow sodium to rush into and thus reversing charge inside the neurons. After about one millisecond the permeability of neurons cell membrane changes and the cells return to their original negative charge inside. But in this process a charge explodes. After each charge explosion the neurons remain refractory for a few milliseconds to changes in permeability limiting to 200 per second or less the rate at which action potentials can be generated.

The current generated by neurons needs boosting on its way and thus the speed of their travel is about 100 meters per second which is only one-millionth of the speed of an electrical signal. Most often communication between neurons is mediated by chemical transmitters that are released at specialized contacts called synapses. When an action potential arrives at the axon terminal, transmitters are released from small vesicles (pouches) to a cleft of about 20 nanometers that separates pre and post synaptic membranes. After their release the chemical neurotransmitters alter the permeability of post-synaptic membrane allowing entering of the electrical current to prove stimulant; conversely, the chemical transmitters may inhibit further transport across to act as inhibitors. Each synapse produces only a small effect and it is the overall all effect of different chemical transmitters that produces a response. There are about 50 neurotransmitter chemicals identified so far. Their role has evolved into many drug actions and diseases of brain. For example, drugs like Valium alleviate anxiety by increasing levels of gamma aminobutyric acid (GABA) in the brain. Actions of cocaine are mediated through the transmitter dopamine. Nicotine in cigarettes alters acetylcholine levels. Many a diseases of the past have lost their stigma because now we know that they are caused by chemical imbalance in the brain; such as schizophrenia.

The efficacy of transmission at synaptic level is what makes all the difference. Drugs are synthesized to alter this with remarkable effects. Some of the delayed effects of drugs are associated with more than transient changes in the synaptic membranes including sprouting of new endings of axons remodeling their behavior. Short term changes associated with simple forms of learning are accompanied by molecular modifications of proteins. The changes can be for life time. The old age of "use it or lose it" seems to have a great deal of credibility in the working of mind.

The initial stages of axon outgrowth and pathway selection are thought to occur independently of activity; the genetically determined part of the program completes the wiring diagram during embryonic life. Once the advancing tips of the axons arrive where they are supposed to be, the choice of exact targets are influenced by nerve impulses originating within the brain or stimulated by events in the world itself. (Steroids influence the formation of synapse during early development of certain regions of brain producing differences in the brain of males and females.)

Information across neurons is not sent on single pathways; there are often multiple channels of communication both ways. The brain is never at rest; with changes in its present activity, blood flow to different part changes. Language is a three-part system: word formation, concept representation and mediation between the two. Study of patients struck with stroke or similar diseases tells us how efficiently the system of language evolved in man.

Mental processes are correlated with electrical signals. It is the complex dancing of all neurons simultaneously that creates mind.

The Developing Brain

During the first few weeks after fertilization many of the sense organs are not connected to brain. Neurons must be generated in sufficient quantity and at right place to complete the wiring. The blue print of this wiring and brain's structure are recorded in genes that express themselves efficiently. At birth all neurons are placed with no further increase in their number possible but the size of brain is only one-fourth of the adult size. Axons grow in size with branching and only a small number of new neurons are formed. To achieve the precision of adult pattern brain must be stimulated somehow. Infants and children must be stimulated through touch, speech and images to develop fully. However, overt stimulation does not increase the process beyond what is its natural growth rate. The axons have specialized tips called growth cones that can recognize the proper pathways. They do so by sensing a variety of specific molecules laid out on the surface of or even released from the cells located along the pathway. The target itself may release the necessary molecular cues. Removing these cues by genetic or surgical manipulations can cause axons to grow aimlessly. Once axons have arrived at their target they still need to select the correct address where many earlier errors can be corrected or made.

The necessity for neuronal activity to complete the development of the brain has distinct advantage. First within limits the maturing nervous system can be modified and fine-tuned by experience itself, thereby providing a certain degree of adaptability. It is also an economical way to design or else all details would have to come in genetic code making it extremely large and difficult to manage? The process of refinement that begins in uterus can protract for quite some time such as seen in the development of vision requiring coordination input from the two eyes for stereoscopic depth perception.

Learning and Individuality

Analysis of learning provides insights into the molecular mechanisms underlying the mental process. Learning is acquiring knowledge and memory is retaining it. Learning produces changes in the nerve cells. The initial information is stored in short-term memory lasting minutes to hours and involves changes in the strength of existing synaptic connections through secondary chemical transmitters. The long term changes lasting for weeks or months are stored at the same site but requiring a totally different mechanism: activation of genes, the expression of new proteins and the growth of new connections. The newer findings now challenge the old that brain structure does not change with time. Small changes both at molecular and at anatomic level occur in the brain continuously constructing what we call our individuality or personality.

Language

Language is our ability to use words or signs and to combine them in sentences so that concepts in our minds can be transmitted to other people. Conversely we also convert spoken words into concepts in our own minds. Language arose and persisted because it serves as a supremely efficient means of communication, especially for abstract concepts. Brain processes language by three interacting sets of structures. Any thing a person does, perceives, thinks or feels is first transmitted to a large collection of neural system in both cerebral hemispheres-the nonlanguage representation. The signals are characterized into different categories and the left cerebral hemisphere begins assembling word-forms and generates sentences and spoken words. A third part of left cerebral hemisphere coordinates the activity of these two centers. This neural machinery is extremely complex. Many questions remains as to how brain stores concepts. Mediation systems for parts of speech other than nouns, verbs and others have been only partially explored. With time these structures will eventually be mapped and understood.

Memory

Working memory, the combination of moment-to-moment awareness and instant retrieval of archived information, is the most significant achievement of human evolution. These operations are carried out in the prefrontal lobes of cerebral cortex, whose dysfunction is not associated with many psychiatric disorders including Parkinson's disease and schizophrenia.

Sexes

Women and men differ not only in physical attributes and reproductive function but also in the way in which they solve intellectual problems. In this day and age of equality of sexes, the liberation movement, it is considered impolite to suggest that these differences are more than the result of experience during development. Sociologists will point out that girls behave different from boys because that's how they are raised are captive to the stereotypical mom to daughter relationship. Unfortunately, facts recently discovered point to a different reality. The two sexes differ in the amount and nature of hormones they carry. The effect of sex hormones on brain organization occurs early in life; environment is acting on differently wired brains in girls and boys. The very premise of studying environmental effects is flawed because of their difference in physiologic disposition. It is like comparing apples and oranges. Studies conducted on the effects of hormones on brain function suggest that throughout life suggest that it is also one of nature's dictum of evolution and survival of species that the two sexes have greater flexibility in their cognitive abilities.

Major sex differences in intellectual function seem to lie in patterns of ability rather than in overall level of intelligence. We know people with similar intelligence are differently adept at for example using words or performing a motor task. Men perform better than women on certain spatial tasks. For example, tasks that require rotating objects or manipulating it in some other way are better performed by men. They also outperform women in mathematical reasoning tests and in navigating their way through a route. (Old Oaken Bucket p 119). They are also more accurate in tests of target-directed motor skills is in guiding or intercepting projectiles.

(A secretary used to communicate with her computer as Hey, You Big Fella. The boss asked, what makes you think the computer is a male. Came the answer because he needs to be told what to do.)

Women are better at rapidly identifying matching items, a skill called perceptual speed. They have greater verbal fluency, including the ability to find words that begin with a specific letter or fulfill some other constraints. They outperform men in arithmetic calculations, recalling landmarks from a route and performing certain precision manual tasks such as placing pegs in designated holes on a board. Though many of these differences appear significantly after puberty, some attribute begin to appear different even at age three such as targeting. It is now confirmed that sex differences in spatial rotation performance are present before puberty.

The differentiation of sexes begins at conception. The genetic material is identical between men and women, except the sex chromosomes. If Y chromosome is present, the fertilized ovum will create testes or male gonads. This is the first critical step towards becoming a male. If the gonads do not produce male hormones, the default form is female. Testosterone produced by gonads promotes development of male ducts and regression of female ducts. If anything goes wrong at any stage of the process the individual may be incompletely masculinized. Besides differentiating genitals, gonadal hormones also shape behaviors. Current studies show that sexual behavior reflects anatomic differences in brain. For example, a specific part of brain interstitial nucleus of the anterior hypothalamus small in homosexual men than in heterosexual men. Sexual preference, it now seems, has a biologic substrate. Homosexual and heterosexual men also perform differently on cognitive tests. The peculiar heterosexual acuity in spatial tests such as throwing a projectile is less developed in homosexual men, who do better at ideational fluency or listing things that were of a particular color.

The effects of hormones on brain appear consequential only at the early stages in life when they alter the brain function permanently. Giving same hormone at later stages in life does little. The hormonal effects go well beyond sexual or reproductive behavior: they appear to extend to all known behaviors in which males and females differ. They seem to govern problem solving, aggression and tendency to engage in rough-and-tumble play. The last behavior is particularly related to dihydrotestosterone working through amygdala in brain. The theories articulating these differences have been proven in animals where they were exposed to hormones during early development. Depriving newborn males of testosterone by castrating them or administering estrogen to newborn female rats results in a complete reversal of sex-typed behavior in the adult animals. Conclusive studies demonstrate that girls exposed to high levels of androgens because of a genetic disorder called congenital adrenal hyperplasia (CAH) or when pregnant women took synthetic steroids, in the prenatal or neonatal stage grow up to be more tomboyish and aggressive than their unaffected sisters. They also selected more typically masculine toys examples cars over dolls and demonstrated better spatial abilities such as discovering a hidden figure within a complex one and rotation tests. There however does not seem to be a linear relationship with amount and extent of exposure.

Though no major changes occur later in life with exposure to hormones, cognitive patterns remain sensitive to hormone fluctuation throughout life. For example, performance of women in doing certain tasks changes throughout the menstrual cycle. With enhanced level of hormones their spatial abilities are depressed while articulation and motor capabilities are enhanced. Men show seasonal variation in their performance also. In spring when testosterone levels are low their performance improves.

How these differences are related to a broader picture of human evolution remains to be determined. To understand why the brains of the two species developed differently we must examine the history of evolution and then conjecture whether the current state of development is relevant to the modern life. Our brain structure has barely changed over the last 50,000 years, yet significant changes in its working have appeared. We lived in small groups of hunter-gatherers. There was a division of labour: men hunted large game which required long-distance travel, defending the group against predators and enemies, shaping and using weapon. Thus developed in men route-finding ability and targeting skills. On the other hand women most probably gathered food near the camp, tended the home, prepared food and clothing and cared for children. This required short-range navigation, perhaps using landmarks, fine motor capabilities to carry out tasks in circumscribed space and perceptual discrimination sensitive to small changes in the environment or in children's appearance or behavior.

Men and women have different occupational interests and abilities hard-wired into their brain and these are barely affected by sociologic influences. Demands of the modern life carve these abilities and interests but the basic difference remains.

Brain Disorders

Madness has been for centuries considered an affliction of the spirit by religion and poetry and as an affliction of various humors and organs of the body by medicine. In the present context we define madness as two chronic disorders and mania. Each of these disorders affects about one percent of our population. An schizophrenic hallucinates, does crazy things, gets depressed, frightened, confused and is unable to perform everyday tasks. The condition deteriorates with age. Mania or mood disorders are distinct from schizophrenia, can be unipolar where the patient has episodes of depression alone which can become so severe that they lead to suicides and bipolar when there are episodes of both mania or state of excitement and depression characterized by impulsive behavior which can ruin marriages, careers and fortunes.

Both schizophrenia and mania are diseases that run in the family or that they have genetic connection. Environmental factors push those who are predisposed to these disease into full blown disorders. People born with these disorders have real differences in their brain structure. The new techniques of CATSCAN and MRI show that the lateral cerebral ventricles are much larger in crazy people than in normal people. The parts of brain which modulate emotional response, memory and other functions are different in crazy people. These differences appear as a result of failure of growth of neurons and development of their connection or from disturbances in the pruning of neurons that normally occur between the ages of three and 15.

Much of the drug discovery to treat these disorders has come serendipitous. Chlorpromazine was developed in the 1950s as an anesthetic but alleviated the symptoms of schizophrenia and mania; there followed the clue to the synthesis of imipramine, still one of the most widely used drug. In 1949, an Australian psychiatrist, John Cade, noted that lithium salts sedated rodents; thus came use of lithium in mania. The mechanism of how antidepressants work began to unfold after the discovery of reserpine derived from a traditional plant from south Asian region by a renowned Pakistani, Dr. Salimuzzaman Siddiqui. Reserpine was one of the first medication for high blood pressure but it also caused severe depression and even suicides. It was found that reserpine depletes the nerve ending of the essential chemical transmitters called monoamines (this include norepinephrine, dopamine and serotonin. In the mid-60s efforts were made to synthesize drugs that will keep high levels of these chemical transmitters and nerve junctions either by increasing their production or by protecting their destruction and reabsorption or reuptake. Later when drugs were discovered that did not fit this theory, discoveries were made of specific receptors attachment to which produces certain secondary chemicals. All of this point out to the observation that many kinds of biological defects pay a part in mania including abnormal receptors and related molecules.

Deterioration of mental disorders with time suggests a process of kindling whereby the triggering signal needed with each succeeding episode is of lesser intensity. After each episode patients respond less to medication found effective earlier.

Schizophrenia is characterized by higher proportion of dopamine neurons and less of glutamate neurons. Classic amphetamines which produce psychosis with chronic use stimulate dopamine release.

Depression also is accompanied by high levels of a hormone cortisol which is released during stress. Thus a system

Aging

Lord Jaques enumerates seven ages of man concluding with the sad description:

Last scene of all, that ends this strange eventful history,

Is second childishness and mere oblivion. (Shakespeare, As You Like It).

The stereotypical devastating decline of brain with age is wrong. With age certain molecules and cells in the brain become increasingly impaired or disappear which can disrupt cognition if accumulated past a critical threshold but this build up by no means automatically accompanies longevity. Older adults who lose their mind do it because of advancing mental disorders like Alzheimer's disease, Parkinson's disease or multiple minor strokes. Some parts of brain are more prone to age-related damage than others and their effects are all dramatically different from person to person. Many other factors of exogenous nature such as use of medications, emotional depression, vitamin B12 deficiency, chronic alcoholism, tumors and infections of the brain, blood clots in brain and metabolic imbalances (including thyroid, kidney or liver disorders) play a significant role in old age dementia.

Senility whereas it brings in the wrath of old age, it is by no means a molecular order.