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The Bipolar Hippocampus

aavanGogh_1888_PontLAngloisA Vanderbilt University study just published in the Archives of General Psychiatry reveals that hippocampal interneurons are modified by bipolar depression. The hippocampus is an important component of the limbic system that acts as the switching center through which incoming sensory signals are retransmitted and initiate behavioral reactions for different purposes. Its importance has been demonstrated empirically: experimental artificial stimulation of the hippocampus can induce a wide variety of behavioral patterns such as pleasure, rage, passivity, or excessive sexual drive. Because of its central function in the modulation of emotions, the hippocampus is believed to have a role in mood disorders such as depression. Numerous postmortem studies conducted on the brain of individuals who were affected by bipolar disorder have shown a decreased density and decreased gene expression of hippocampal interneurons. These findings, however, had not been confirmed by neuroimaging studies of hippocampal volume and function in live subjects—until now.

hippocampal_anatomyTo assess hippocampal volume, neuron number, and interneurons the Vanderbilt study examined sample brain specimens of hippocampi from 14 individuals with bipolar disorder and compared them to those taken from 18 healthy control subjects. The specimens, provided by the Harvard Brain Tissue Resource Center at McLean Hospital, were cut at 2.5-mm intervals and sections from each tissue slice were either Nissl-stained or stained with antibodies against somatostatin or parvalbumin. Messenger RNA was extracted from fixed tissue and real-time quantitative polymerase chain reaction was performed.

The researchers analyzed each sample by measuring the volume of pyramidal and nonpyramidal cell layers, overall neuron number and size, number of somatostatin- and parvalbumin-positive interneurons, and messenger RNA levels of somatostatin, parvalbumin, and glutamic acid decarboxylase 1.

After comparing healthy and unhealthy hippocampal samples, the study showed that the 2 groups did not differ in the total number of hippocampal neurons, but the bipolar disorder group showed reduced volume of the nonpyramidal cell layers, reduced somal volume in cornu ammonis sector 2/3, reduced number of somatostatin- and parvalbumin-positive neurons, and reduced messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1.

According to the researchers, these results indicate a specific alteration of hippocampal interneurons in bipolar disorder, which is likely to produce a hippocampal dysfunction that can have, among other manifestations, an effect on the onset and severity of bipolar depression.

Stress and the Female Brain Advantage

drlouannbrizendineIn 1994, Louann Brizendine, a neuropsychiatrist at the University of California, established the Women’s Mood and Hormone Clinic in San Francisco—one of very few such institutions in the world—and focused her attention on the etiology and functioning of the female nervous system.

In 2007, she published The Female Brain as the culmination of her 20 years of research and a compendium of the latest findings from a range of disciplines. It is a fascinating and, in some ways, startling revelation of the most noteworthy particularities that characterize the human female brain.

Size Does Matter… and So Does Density

Women and men have very nearly the same number of brain cells, even though the female brain is about 9% smaller than men’s. This fact had been known for some time and had been, more or less jokingly, interpreted as meaning that women were not as smart. Dr. Brizendine reveals a much simpler explanation: women’s brain cells are more tightly packed into the skull.

To further dispel any notion of masculine brain superiority, she says, women have 11% more language and hearing neurons than men and a larger hippocampus, the area of the brain that is most closely associated with memory. Much more developed in female brains than male’s is also the circuitry for observing emotion on other people’s faces. Dr. Brizendine concludes that, when it comes to speech, emotional intelligence, and the ability to store richer and more detailed memories, women appear to possess a richer brain endowment and thus a natural advantage.

The amygdala in males, on the other hand, has far more processors than in females, which could explain men’s greater intensity in perceiving danger and their higher proneness to aggression. The male body is much quicker to mobilize to anger and take violent action in reaction to an immediate physical danger.

Are women not as capable of reacting to danger? Dr. Brizendine says that a woman’s brain is as capable to perceive danger or deal with life-threatening situations, but that it mobilizes the body’s resources in quite a different way. The female brain appears to be wired to perceive greater stress over the same event than a man’s. This greater arousal and more forceful stress reaction appears to be a natural way to ensure adequate protection against all possible risks to her children or family unit. Brizendine suggests that this ancestral reason may account for the way a modern woman may view unpaid bills as catastrophic and naturally perceive them more intensely threating to the family’s very survival.

[amtap book:isbn=0767920104]

MRI scans have pushed knowledge much higher by allowing the observation of the workings of the brain in real time. The brain lights up in different places depending on whether it is stimulated by love, looking at faces, solving a problem, speaking, or experiencing anxiety. What lights up, where and when, is different between men’s and women’s brains. Women use different parts of the brain and different circuits to accomplish the same tasks, including solving problems, processing language, and generally experiencing the world.

This is a fascinating book for the scientist and the novice alike, well worth reading. It is the Stresshacker Recommended selection for this month.

Stress Hardware Update: Limbic System 2.0

LimbicSystemGeographyThe term limbic system designates the entire neuronal circuitry and forebrain structures that control emotional behavior, motivational drives and the processing of present and past sensory experiences. The brain structures of the limbic system are located around the middle edge of the brain. Several limbic structures are involved in determining the affective nature of sensory inputs, i.e., whether the sensations are pleasant or unpleasant. The emotional qualities we attach to the input provided by our five senses are also called reward (when they are pleasing to us and therefore we crave more of them) or punishment (when they are unpleasant and therefore we seek to avoid them), or satisfaction or aversion. Neurobiological research on the functions of the limbic system dating back to its XIX century pioneer Pierre-Paul Broca (1861), later expanded by James Papez (1937), Giuseppe Moruzzi and Horace Magoun (1949), and Ross MacLean (1949, 1952) identified the “reticular” and “limbic” systems as regulating the energizing and expressive roles in the central nervous system.

The limbic system is comprised of numerous structures, the most important of which are the hypothalamus, the amygdala, the hippocampus, the cortex, the cingulate gyrus, the striatum, the pallidum, the thalamus, and Meynert’s nucleus basalis. Each of these structures performs a specific function, and often also serves to receive, transmit and amplify communication within the limbic system, with other areas of the brain, and with other parts of the central nervous system.

The Hypothalamus: The Central Autonomic Controller

A major component of the limbic system is the hypothalamus and its related substructures. The hypothalamus complex controls the internal state of the body, such as temperature, osmolality of the body fluids, appetite and thirst and the regulation of body weight. Despite its very small size of only a few cubic centimeters (which represents less than 1% of the brain mass), the hypothalamic complex has two-way communicating pathways with all levels of the limbic system and is the key structure for higher level coordination of autonomic and endocrine functions. There would not be a stress reaction, with its almost instantaneous activation of physical and psychological defense mechanisms, without the hypothalamus providing the critical signal activation.

The Amygdala: The CPU of Emotional Response

AmygdCingGyrusThe amygdala is a group of nuclei embedded in the anteromedial temporal lobe, which receives input from all five senses. It performs the analysis of form and color and facilitates the recognition of complex stimuli such as human faces. The amygdala can influence heart rate and blood pressure, gut and bowel function, respiratory function, bladder function, and many more instinctive physical reactions. It is in the amygdala and its connection to other limbic structures that the determination of the affective value of sensory stimuli (rewarding or aversive) is made and our mood (or feelings about something) is determined. Stimulation of the amygdala produces the defense reaction that prepares us for fight, flight or freeze, along with complex sensory and experiential phenomena, which may include fear, sensory hallucinations, feelings of deja vu, and memory-related flashbacks and nightmares. The amygdala receives neuronal signals from all portions of the limbic cortex and is the “central processing unit” in which the limbic system produces an emotional response to events, people and situations. The amygdala also interacts with higher brain regions that govern such processes as directed attention, declarative memory, and response inhibition (Davidson, Putnam, & Larson, 2000; LeDoux, 1995).

The Hippocampus: Memory Chips and Orientation

The hippocampus is a highly specialized region of the cerebral cortex, which along with surrounding areas of the parahippocampal gyrus is directly involved in memory processing and spatial orientation. The hippocampus provides the neural mechanism for association of different parameters that is necessary for the moment-to-moment incorporation of experience into our short- and long-term memory banks. Almost any type of input from the five senses causes activation of at least part of the hippocampus, which in turn distributes many outgoing signals to the anterior thalamus, to the hypothalamus, and to other parts of the limbic system, especially through the fornix, a major communicating pathway.

The Orbital and Medial Prefrontal Cortex: Food and Personality

PhineasGageThe cortical areas of the limbic system are divided into two interconnected networks with related but distinct functions. Many of these functions are related to food or eating (e.g., olfaction, taste, visceral afferents, somatic sensation from the hand and mouth, and vision), and neurons in the orbital cortex respond to multisensory stimuli involving the appearance, texture, or flavor of food. Therefore, the orbital and medial prefrontal cortex have the function of evaluating feeding-related sensory information and to stimulate appropriate visceral reactions. More importantly, damage to the ventromedial frontal lobe can produce dramatic behavioral changes, which suggests that the visceral reactions evoked through this cortical area are critical in evaluating alternatives and making choices. As the well-publicized 19th-century case of Mr. Phineas Gage’s accidental head impaling by a steel rod demonstrates, individuals with damage to the ventromedial prefrontal cortex have no problem with their motor or sensory function, their intelligence or cognitive function, but show devastating changes in personality and choice behavior.

The Cingulate Gyrus: The Cement of Society

Intriguing data and ideas have been proposed by several researchers seeking to identify specific functions of the cingulate gyrus. In what has been termed the affiliation/attachment drive theory, Everly (1988) has shown experimentally that the removal of the cingulate gyrus eliminates both affiliative and grooming behaviors. MacLean (1985) has argued that the affiliative drive may be hard-coded in the limbic system and may be the anatomical underpinning of the “concept of family” in humans and primates. The drive toward other-oriented behaviors, such as attachment, nurturing, affection, reliability, and collaborative play, which has been referred to as the “cement of society” (Henry and Stephens, 1977), appears to originate in this relatively small limbic system structure.

The Ventromedial Striatum, Ventral Pallidum, and Medial Thalamus

The nuclei of the ventromedial striatum are also related to reward and reward-related behavior, whereby they inhibit or suppress unwanted behaviors while allowing other behaviors to be freely expressed. The dorsolateral striatum and related areas of the globus pallidus appear to be involved in switching between different patterns of motor behavior, whereas the ventromedial striatum and pallidum may allow changing of stimulus–reward associations when the reward value of a stimulus has changed. These areas are examples of the complexity and redundancies built into limbic system structures that permit multiple iterations of signal transmission and reception, and a much more complex and refined analysis of sensory inputs from the five senses.

Nucleus Basalis (of Meynert)

The nucleus basalis of Meynert is a prominent group of large cells located in the basal forebrain, most of which are involved in the activation of acetylcholine or GABA neurotransmitters, indispensable in activation of the stress reaction and our defense mechanism when a physical or psychological threat is perceived. The magnocellular basal forebrain nuclei are well situated to modulate brain activity in relation to limbic activity.

Disorders of the Limbic System

Although lesions to limbic structures do not necessarily result in sensory or motor deficits, any loss of function in these structures is usually associated with a variety of psychological problems, including depression, bipolar disorder, obsessive–compulsive disorder, and schizophrenia.

Structural changes have been noted in the hippocampal formation, medial thalamus, and prefrontal cortex in schizophrenic subjects. Images obtained through positron emission tomography scans show that the amygdala, prefrontal cortex and medial thalamus are abnormally active in patients suffering from severe unipolar and bipolar depression.

The complete removal of the amygdala and other nearby structures in laboratory settings causes specific changes in animal behavior called the Klüver-Bucy syndrome, whose characteristic symptoms are a complete lack of fear of anything, extreme curiosity about everything, rapid loss of short-term memory, tendency to place everything in the mouth and sometimes even trying to eat solid objects, and a sex drive so strong that it leads to attempts to copulate with immature animals, animals of the wrong sex, or even animals of a different species. Although similar lesions in human beings are rare, afflicted people respond in a manner not too different from that of the affected animal.

Stress Hardware Reviews: The Hippocampus

clip_image001What brain structures rouse us from inactivity and set in motion our defense mechanisms when a stressor is perceived? Predictably, the brain’s older and more primordial area, the so-called animal brain, where the hypothalamus, the amygdala, the hippocampus, the septum area, the basal ganglia and the thalamus are located. These structures, collectively called the limbic system, are interconnected and work together to initiate motor and other functional activities of the brain that mobilize the body. In this post about stress hardware, we discuss the hippocampus.

Virtually any experience perceived by the five senses appears to cause the activation of at least some part of the hippocampus. The hippocampus in turn redistributes these sensory signals to the thalamus, the hypothalamus, and other parts of the limbic system. Thus, the hippocampus acts as an important switching center through which incoming sensory signals are retransmitted and initiate behavioral reactions for different purposes. Its importance has been demonstrated empirically: experimental artificial stimulation of the hippocampus can induce a wide variety of behavioral patterns such as pleasure, rage, passivity, or excessive sexual drive.

The cells of the hippocampus appear to be especially sensitive to the effects of various stressors. Although not directly involved in the stress response, its ventral regions appear to exercise a regulatory influence on the hypothalamic-pituitary-adrenal (HPA) axis activity and are also a primary target for elevated glucocorticoid levels. The glucocorticoid hormones owe their name to their important effects on blood glucose concentration, which is the principal source of energy of the human cell. They also regulate protein and fat consumption, and the utilization of carbohydrates to produce additional quantities of energy. Cortisol is the principal glucocorticoid. Read more