The Fractal Geometry of the Human Brain: An Evolutionary Perspective.

The evolution of the brain in mammals is characterized by changes in size, architecture, and internal organization. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development. In this chapter, some of the design principles and operational modes that underlie the fractal geometry and information processing capacity of the cerebral cortex in primates, including humans, will be explored. It is shown that the development of the cortex coordinates folding with connectivity in a way that produces smaller and faster brains.

On the nature and evolution of the human mind.

Organisms are faced during their lives with an immense variety of environmental challenges and organism specific problems, for which they have to find adequate solutions in order to survive. Problem solving, in other words, is an essential dynamic survival mechanism, evolved to cope with disturbances in the ecological equilibrium. With the evolution of sensory systems as adaptations to specialized environments, the capacity to process large amounts of sensory information increased and, with that, the power to create more complex models of reality. The object of this review is to present current perspectives on the organization and evolution of the human brain and to examine some of the design principles and operational modes that underlie its information processing capacity. Furthermore, the neural correlates of mind-the set of cognitive faculties involved in perceiving, remembering, reasoning and deciding-will be explored. It will be argued that in primates, and especially humans, the complexity of the neural circuitry of the cerebral cortex is the neural correlate of higher cognitive functions, including mind-like properties and consciousness.

Evolution of the human brain: when bigger is better.

Comparative studies of the brain in mammals suggest that there are general architectural principles governing its growth and evolutionary development. We are beginning to understand the geometric, biophysical and energy constraints that have governed the evolution and functional organization of the brain and its underlying neuronal network. The object of this review is to present current perspectives on primate brain evolution, especially in humans, and to examine some hypothetical organizing principles that underlie the brain's complex organization. Some of the design principles and operational modes that underlie the information processing capacity of the cerebral cortex in primates will be explored. It is shown that the development of the cortex coordinates folding with connectivity in a way that produces smaller and faster brains, then otherwise would have been possible. In view of the central importance placed on brain evolution in explaining the success of our own species, one may wonder whether there are physical limits that constrain its processing power and evolutionary potential. It will be argued that at a brain size of about 3500 cm(3), corresponding to a brain volume two to three times that of modern man, the brain seems to reach its maximum processing capacity. The larger the brain grows beyond this critical size, the less efficient it will become, thus limiting any improvement in cognitive power.

The Central Institute for Brain Research in Amsterdam and its directors.

The Central Institute for Brain Research was founded in Amsterdam in 1908 as part of an international effort to study the nervous system with multiple institutions and various disciplines. The development of research in the past hundred years at the Brain Institute has hardly been documented. We analyze the history of this institute by means of brief portraits of its directors and their main research topics. It appears that each director introduced his own branch of neuroscience into the institute. Initially, mainly comparative neuroanatomical data were collected. Following the Second World War, the multidisciplinary approach slowly developed with research programs on systems neuroscience, neuroendocrinology, and brain disorders. Every new director introduced new approaches to the study of the brain and thus played an important role in keeping brain research in the Netherlands at the international forefront where it has been ever since its foundation in 1908.

Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases.

STUDY OBJECTIVES: Neuronal histamine shows diurnal rhythms in rodents and plays a major role in the maintenance of vigilance. No data are available on its diurnal fluctuation in humans, either in health or in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD), or Huntington disease (HD), all of which are characterized by sleep-wake disturbances. DESIGN: Quantitative in situ hybridization was used to study the mRNA expression of histidine decarboxylase (HDC), the key enzyme of histamine production in the tuberomammillary nucleus (TMN) in postmortem human hypothalamic tissue, obtained from 33 controls and 31 patients with a neurodegenerative disease-PD (n = 15), AD (n = 9), and HD (n = 8)-and covering the full 24-h cycle with respect to clock time of death. RESULTS: HDC-mRNA levels in controls were found to be significantly higher during the daytime than at night (e.g., 08:01-20:00 versus 20:01-08:00, P = 0.004). This day-night fluctuation was markedly different in patients with neurodegenerative diseases. CONCLUSION: The diurnal fluctuation of HDC-mRNA expression in human TMN supports a role for neuronal histamine in regulating day-night rhythms. Future studies should investigate histamine rhythm abnormalities in neurodegenerative disorders. CITATION: Shan L; Hofman MA; van Wamelen DJ; Van Someren EJW; Bao AM; Swaab DF. Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases.

Design principles of the human brain: an evolutionary perspective.

The evolution of the brain in mammals has been accompanied by a reorganization of the brain as a result of differential growth of certain brain regions. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development and that the primate neocortex is uniformly organized and composed of neural processing units. We are beginning to understand the geometric, biophysical, and energy constraints that have governed the evolution of these neuronal networks. In this review, some of the design principles and operational modes will be explored that underlie the information processing capacity of the cerebral cortex in primates, and it will be argued that with the evolution of the human brain we have nearly reached the limits of biological intelligence.

Neuronal histamine production remains unaltered in Parkinson's disease despite the accumulation of Lewy bodies and Lewy neurites in the tuberomamillary nucleus.

Neuronal histamine production in the hypothalamic tuberomamillary nucleus (TMN) was hypothesized to change significantly in Parkinson's disease (PD) in relation to the accumulation of Lewy bodies/Lewy neurites (LBs/LNs). We measured the messenger ribonucleic acid (mRNA) levels of histidine decarboxylase (HDC), the key enzyme of histamine production, and the amount of LBs/LNs in the TMN by quantitative in situ hybridization and immunocytochemistry in postmortem human brain material of clinical PD (CPD), preclinical PD, and control subjects. No significant difference of histidine decarboxylase mRNA levels was observed among different clinical or Braak-PD stages, in spite of the strong accumulation of LBs/LNs in the TMN of clinical PD patients. We conclude that neuronal histamine production remains largely unaltered in PD despite the abundant LB/LN accumulation in the TMN.

The C. U. Ariëns Kappers brain collection.

The C. U. Ariëns Kappers brain collection, at the Netherlands Institute for Neuroscience in Amsterdam, is one of the largest and oldest of the world's catalogued repositories of specimens that reveal the course of brain evolution and the resulting panoply of neural biodiversity. Established a century ago, it has served since then as the basis of the encyclopedic texts authored by its founder, as well as research publications into the current time. It consists of 726 specimens: these include 309 mammals, 134 birds, 81 reptiles, 21 amphibians, and 179 "pisces"--a grouping of bony fish, sharks, and cyclostomes. We present here accounts of the history and contents of this treasure trove of research materials.

Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress.

OBJECTIVE: Corticotropin-releasing hormone (CRH) plays an important role in neuroendocrine, autonomic and behavioral responses to stressors. In the present study, the effect of chronic unpredictable mild stress (CUMS) on CRH neurons was investigated in rat brain. METHODS: The rats were exposed to one of the stressors each day for 21 d. Immunostaining was performed to detect the CRH-positive neurons in the paraventricular nucleus (PVN) of the hypothalamus and in amygdala. RESULTS: After the stress protocol, the animals showed a reduction in body weight gain as well as reduced sucrose preference and locomotor activity. Interestingly, the CRH neurons in both PVN and central nucleus of the amygdala (CeA) were stimulated by CUMS. The densities of CRH-containing neurons in both PVN and CeA were significantly higher than those in control group. CONCLUSION: The CRH systems in PVN and CeA may both contribute to depression-like behaviors during CUMS.

Relation between corticotropin-releasing hormone neuron number in the hypothalamic paraventricular nucleus and depressive state in Alzheimer's disease.

BACKGROUND/AIMS: Depression occurs in 20-50% of the Alzheimer disease (AD) patients. It is not known whether depression in AD shares its pathophysiology with depressive disorder. Previously we found a fourfold increase of corticotropin-releasing hormone (CRH)-immunoreactive (IR) neurons in the hypothalamic paraventricular nucleus in depression. The objective of the present study was to find out whether in depression in AD the same phenomenon of an increased number of CRH-IR neurons could be observed. METHODS: Post-mortem brain tissue was obtained from a cohort of 23 AD patients prospectively studied using the Cornell Scale for Depression in Dementia to measure depressive symptoms. The number of CRH-IR neurons was determined using immunocytochemistry and the Image Pro Plus analysis program. RESULTS: A significant positive correlation was found between the Cornell scores and the number of CRH-IR neurons (p = 0.039) in AD patients. CONCLUSION: These results suggest that depressive disorder and depression in AD share, at least partly, their pathophysiology.

Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: A preliminary report.

BACKGROUND: Elevated arginine vasopressin (AVP) plasma levels have been observed in major depression, particularly in relation to the melancholic subtype. Two hypothalamic structures produce plasma vasopressin: the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). The aim of this study was to establish which structure is responsible for the increased vasopressin plasma levels in depression. METHODS: Using in situ hybridization, we determined the amount of vasopressin messenger ribonucleic acid (mRNA) in the PVN and SON in postmortem brain tissue of nine depressed subjects (six with the melancholic subtype) and eight control subjects. RESULTS: In the SON, a 60% increase of vasopressin mRNA expression was found in depressed compared with control subjects. In the melancholic subgroup, AVP mRNA expression was significantly increased in both the SON and the PVN compared with control subjects. CONCLUSIONS: We found increased AVP gene expression in the SON in depressed subjects. This might partly explain the observed increased vasopressin levels in depression.

Increased cerebrospinal fluid cortisol level in Alzheimer's disease is not related to depression.

Hypothalamo-pituitary-adrenal (HPA)-axis hyperactivity is well established in a large proportion of both Alzheimer's disease (AD) patients and idiopathic depression patients, resulting in, e.g. increased cerebrospinal fluid (CSF) cortisol levels. We hypothesized that HPA-axis activity in depressed AD patients is even more increased than in non-depressed AD patients, resulting in higher CSF cortisol levels. Cortisol levels were measured in post mortem CSF of depressed and non-depressed AD patients and in controls. Cortisol levels in AD patients were more than double those of controls, while no significant differences were found between depressed and non-depressed AD patients. These results suggest a different pathogenetic mechanism in depression in AD than in idiopathic depression.

Living by the clock: the circadian pacemaker in older people.

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be a critical component of a neural oscillator system implicated in the timing of a wide variety of biological processes. The circadian cycles established by this biological clock occur throughout nature and have a period of approximately 24 h. With advancing age, however, these daily fluctuations deteriorate, leading to disrupted cycles with a reduced amplitude. In humans, age-related changes have been described for hormonal rhythms, body core temperature, sleep-wakefulness and several other behavioral cycles. It appears that the disruption of circadian rhythms and the increased incidence of disturbed sleep during aging are paralleled by age-related alterations in the neural and temporal organization of the SCN and a decreased photic input to the clock. The many lines of evidence of age-related decrements in circadian time-keeping and the observed neuronal degeneration of the SCN in senescence strongly suggest that the circadian pacemaker in the human brain becomes progressively disturbed during aging.

The brain's calendar: neural mechanisms of seasonal timing.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal component of the mammalian biological clock, the neural timing system that generates and coordinates a broad spectrum of physiological, endocrine and behavioural circadian rhythms. The pacemaker of the SCN oscillates with a near 24 h period and is entrained to the diurnal light-dark cycle. Consistent with its role in circadian timing, investigations in rodents and non-human primates furthermore suggest that the SCN is the locus of the brain's endogenous calendar, enabling organisms to anticipate seasonal environmental changes. The present review focuses on the neuronal organization and dynamic properties of the biological clock and the means by which it is synchronized with the environmental lighting conditions. It is shown that the functional activity of the biological clock is entrained to the seasonal photic cycle and that photoperiod (day length) may act as an effective zeitgeber. Furthermore, new insights are presented, based on electrophysiological and molecular studies, that the mammalian circadian timing system consists of coupled oscillators and that the clock genes of these oscillators may also function as calendar genes. In summary, there are now strong indications that the neuronal changes and adaptations in mammals that occur in response to a seasonally changing environment are driven by an endogenous circadian clock located in the SCN, and that this neural calendar is reset by the seasonal fluctuations in photoperiod.

Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression.

To investigate whether depression is accompanied by changes in diurnal rhythms of free estradiol and cortisol in different phases of the menstrual cycle, we measured these two hormone levels in saliva samples collected every 2 h for 24 h from 15 healthy normally cycling women and 12 age-matched normally cycling women suffering from major depression taking antidepressants. The assessments were repeated four times over one menstrual cycle: during menstruation and in the late follicular/peri-ovulating, early to mid-luteal and late luteal phases, respectively. Quantification with a nonlinear periodic regression model revealed distinct diurnal rhythms in free estradiol and free cortisol in all subjects. For the diurnal cortisol rhythm, significant differences were found in the peak-width and ultradian amplitude among different menstrual phases, both in controls and depressed patients, while no significant differences were found between the two groups. The diurnal estradiol rhythm, on the other hand, was quite consistent among different menstrual phases within both groups, while the depressed patients had overall larger amplitudes than controls, which is negatively correlated with disease duration. Significant positive correlations between the two hormone rhythms were found for 24-h mean level (mesor), peak, and trough in late luteal phase, and for ultradian harmonics in early to mid-luteal phase in controls, but only for ultradian harmonics in late follicular/peri-ovulating phase and for acrophase in the menstruation phase in depressed patients. A sub-analysis was also performed in patients who received Fluoxetine (n = 7). The findings implicate a close correlation between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, both of which may be involved in depression.

Changes in diurnal rhythms of free cortisol secretion during different phases of menstrual cycle.

The effect of the menstrual cycle on the diurnal cortisol rhythm was investigated in 15 normally cyclic healthy women during reproductive life. Salivary cortisol was measured by radioimmunoassay in samples collected every 2 h for 24 h during the four phases of the menstrual cycle: menstrual phase, late follicular/peri-ovulation phase, early to mid luteal phase and late luteal phase, respectively. Distinct diurnal rhythms of free cortisol were found throughout the menstrual cycle by using a nonlinear periodic regression model. The model was characterized by an asymmetrically peaked diurnal cycle and ultradian harmonics. There was a trend to higher troughs and significantly shorter peak-width in phase II and phase IV compared to phase I. The ultradian amplitude in phase IV was significantly lower compared with phase I and showed a trend of decrease compared with phase II. The results suggest that the daily cortisol secretion is modulated by the phase of the menstrual cycle.

Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels.

Neuropathology is the most reliable criterion for diagnosing Alzheimer's disease (AD). A well-established system for staging the spread of neuropathological changes in AD is available. The clinical use of a biomarker that reflects the neuropathological change occurring in brain tissue has not yet been established. Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in AD. Melatonin levels were determined in ventricular postmortem cerebrospinal fluid (CSF) of 121 subjects. Braak staging and a modified Braak staging for cortex (MBSC) were used to evaluate the severity of AD neuropathology. The present study revealed that not only the Braak stages of AD, but also the MBSC were negatively correlated with CSF melatonin levels. By using MBSC, we now demonstrate for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts. Those individuals that did not have any neurofibrillary tangle (NFT) or neuritic plaque (NP) in the temporal cortex, had much higher melatonin levels (287 +/- 68 and 280 +/- 64 pg/mL, respectively) than those individuals that had a few NFTs and NPs (82 +/- 4 and 39 +/- 8 pg/mL, respectively) in the temporal cortex. These results suggest that the decrease in CSF melatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms.

Sex differences in the hypothalamus in the different stages of human life.

Quite a number of structural and functional sex differences have been reported in the human hypothalamus and adjacent structures that may be related to not only reproduction, sexual orientation and gender identity, but also to the often pronounced sex differences in prevalence of psychiatric and neurological diseases. One of the recent focuses of interest in this respect is the possible beneficial effect of sex hormones on cognition in Alzheimer patients. The immunocytochemical localization of estrogen receptors (ER) alpha, beta and androgen receptors has shown that there are indeed numerous targets for sex hormones in the adult human brain. Observations in the infundibular nucleus have, however, indicated that in this brain area the hyperactivity resulting from a lack of estrogens in the menopause seems to protect females against Alzheimer changes, in contrast to males. It is thus quite possible that estrogen replacement therapy may, in these brain areas, lead to inhibition of neuronal metabolism and thus to the same proportion of Alzheimer changes as are observed in men. Knowledge about the functional sex differences in the brain and the effect of sex hormones on neuronal metabolism may thus provide clues not only for the possible beneficial effects of these hormones (e.g., on cognition or hypertension), but also on possible central side effects of estrogen replacement therapy.