Comprehensive Notes on Anatomical and Physiological Foundations of Psychic Activity

Research Methods in Psychobiology

The study of the nervous system is one of the most complex areas of neuroscience because the brain is the most difficult organ to observe directly. Psychobiologists utilize a vast array of methods, classified primarily by the subject type: preclinical research (conducted on animals) and clinical research (conducted on humans). Techniques are further divided into invasive and non-invasive methods, depending on whether they involve direct intervention in brain tissue. Modern neuroscientific research increasingly aims to reduce invasiveness, favoring methods that allow for the study of the living human brain in vivo without surgical intervention, collectively known as neuroimaging.

Historically, observing the living human brain was limited. Conventional radiography was ineffective for brain study because different cerebral structures absorb X-rays in very similar ways, making it impossible to distinguish between areas. Radiography relies on an X-ray beam passing through an object; it is effective when there are marked differences in absorption (such as between bone and soft tissue) but fails in the brain. To overcome this, contrast radiography was developed, involving the injection of a radiopaque substance that absorbs X-rays more than surrounding tissues. An example is cerebral angiography, which visualizes the cerebral vascular network to identify vascular damage, circulatory malformations, or tumors that displace blood vessels. Changes in the shape of ventricles or the cortex can also indicate degenerative processes or anomalous masses.

Computed Tomography (CT or TAC), introduced in the early 1970s, represented a decisive step forward. It is a computer-assisted radiological technique where a patient lies inside a cylinder while an X-ray tube rotates around the head, emitting beams from various angles. A computer integrates this data to reconstruct horizontal sections of the brain. By repeating this at different levels, a three-dimensional representation of the encephalon is obtained. While CT can identify neoplasms, traumas, and hemorrhages, it has lower resolution than Magnetic Resonance Imaging (MRI) and involves exposure to ionizing radiation.

Magnetic Resonance Imaging (MRI) operates on a completely different principle, using a powerful magnetic field rather than X-rays. It relies on the presence of hydrogen atoms in water molecules, which are abundant in biological tissues. In the magnetic field, hydrogen atoms align; when they return to their initial position, they emit radiofrequency signals detected by the machine. Since brain structures contain varying amounts of water, the signals vary, allowing for high-resolution 3D images. MRI offers superior spatial resolution compared to CT and carries no risk from ionizing radiation.

Functional techniques observe which areas activate during specific tasks, based on the principle that active cerebral areas consume more energy, requiring more blood, oxygen, and glucose. Positron Emission Tomography (PET) was the first functional technique. It involves injecting a radioactive tracer, typically fluorodeoxyglucose (FDG), into the carotid artery. Because FDG is similar to glucose, active neurons absorb it, but it is not metabolized and accumulates instead. The radioactivity emits positrons that collide with electrons, causing annihilation and releasing gamma rays. The PET scanner detects these rays to create a color-coded map of metabolic activity. PET is also used to study neurotransmitter and receptor distribution, though it requires radiation and has lower spatial resolution than MRI.

Functional Magnetic Resonance Imaging (fMRI) is currently the most used functional technique. It relies on the BOLD (Blood Oxygen Level Dependent) signal. When a brain area activates, it demands more oxygenated blood than its actual energetic requirement, leading to an increase in oxyhemoglobin relative to deoxyhemoglobin. Since these two states of hemoglobin have different magnetic properties, they alter the local magnetic field. Therefore, fMRI measures blood flow changes linked to neuronal activity rather than electrical activity itself. Advantages include being non-invasive (no injections), providing simultaneous structural and functional data, and superior spatial resolution. However, it has poor temporal resolution, as the BOLD signal takes seconds to record while neuronal activity occurs in milliseconds ($ms$).

Neurodevelopment: From Embryo to Adult

Development begins at fertilization when a sperm and oocyte unite to form a zygote, a single undifferentiated cell. This cell divides rapidly, creating millions of cells that specialize into tissues and organs. Every cell shares the same genotype (genetic makeup), but the phenotype (morphological, physiological, and behavioral traits) varies based on gene expression and environmental factors. DNA contains genes that encode information for protein production. Gene expression involves the transcription of DNA into messenger RNA, which leaves the nucleus to be translated into proteins by ribosomes. This process is influenced by mutations or epigenetic modifications that regulate gene activity without altering the DNA sequence.

Within the first few weeks, the zygote forms a mass of cells interacting with the uterus. After approximately $2-3\,weeks$, gastrulation occurs, arranging cells into three embryonic layers: the Ectoderm (giving rise to the nervous system and skin), the Mesoderm (forming muscles, skeleton, kidneys, and reproductive system), and the Endoderm (forming lungs, digestive system, and glands). The ectoderm develops into the neural plate, which folds to form the neural tube; its edges become the neural crests. The neural tube eventually becomes the spinal cord and encephalon. Failure of the tube to close can result in malformations like spina bifida or anencephaly. The anterior end of the tube develops three swellings: the Prosencephalon, Mesencephalon, and Rhombencephalon.

Neurodevelopment consists of five main phases. First is the induction of the neural plate at about $3\,weeks$ post-conception. Second is neuronal proliferation, where cells in the ventricular and subventricular zones multiply rapidly; radial glial cells act as stem cells for new neurons and migration. Third is migration and aggregation, where cells move to their destination via radial migration (outward from the ventricular zone) or tangential migration (parallel to the tube walls). Migration occurs through soma translocation or along radial glia filaments, guided by chemical signals and supported by cell adhesion molecules (CAMs). Fourth is synaptogenesis, where axons establish connections at a rate of approximately $700,000\,synapses/second$, supported by astrocytes, microglia, and neurotrophins. Fifth is programmed cell death (apoptosis) and synaptic reorganization. About half of the produced neurons are eliminated via apoptosis, a tidy genetic process that prevents the inflammation associated with necrosis. This allows for the selection of effective circuits.

After birth, the brain continues to grow as neurons increase in size, dendrites branch, and synapses multiply. However, starting after the first year, a process called pruning eliminates unnecessary synapses, continuing through adolescence. The prefrontal cortex, vital for behavioral inhibition and planning, matures last. Aging brings a physiological cognitive decline, including reduced processing speed and alterations in the hippocampus, although long-term memory remains relatively preserved. Dementia represents a drastic failure of these cognitive capacities.

General Anatomy of the Nervous System

The vertebrate nervous system is divided into the Central Nervous System (CNS), comprising the brain (encephalon) and spinal cord, and the Peripheral Nervous System (PNS). The encephalon includes the cerebrum (telencephalon and diencephalon), the cerebellum, and the brainstem (mesencephalon, pons, and medulla oblongata). The CNS is protected by the skull and spine, as well as the meninges, which consist of three layers: the robust Dura Mater, the web-like Arachnoid (with the subarachnoid space containing cerebrospinal fluid), and the delicate Pia Mater adhering to the nerve tissue. Meningitis is a pathology of these layers that can lead to permanent cognitive or motor deficits.

Cerebrospinal Fluid (LCS) provides physical protection and cushioning. It fills the subarachnoid space, the central canal of the spinal cord, and the four cerebral ventricles (two lateral, a third, and a fourth). LCS is produced by the choroid plexuses in the ventricles and reabsorbed into the dural sinuses. Obstructions, such as a tumor blocking the cerebral aqueduct, can lead to hydrocephalus. The Blood-Brain Barrier (BEE) is a selective filter protecting the brain, which consumes $20\%$ of the body's energy. Endothelial cells in cerebral vessels are tightly joined to prevent the passage of large molecules while actively transporting glucose. This barrier can be compromised by inflammation or neurodegenerative diseases like Alzheimer's.

The human encephalon weighs between $1,2\,kg$ and $1,4\,kg$. Its dorsal surface is the cerebral cortex, divided into two hemispheres by a longitudinal fissure. They communicate via the corpus callosum. This organization underlies lateralization: the right hemisphere controls the left side of the body and vice versa. The ventral surface includes the cerebellum, brainstem, and the optic chiasm, where optic nerves partially cross. The olfactory bulbs at the front process smell information from the nasal epithelium.

Anatomical divisions from development lead to five major regions. The Telencephalon, the largest part, includes the cerebral cortex and handles complex functions like language and cognition. The Diencephalon contains the Thalamus (sensory relay) and Hypothalamus (regulation of hunger, sleep, and the endocrine system via the pituitary). The Mesencephalon includes colliculi for visual/auditory reflexes and the substantia nigra for movement. The Metencephalon comprises the pons and cerebellum (fine motor control and posture). The Mielencephalon (medulla oblongata) contains the reticular formation, regulating vital reflexes like breathing and heart rate.

Functional Organization of the Brain

The Limbic System regulates emotions, motivation, and memory. Key structures include the Amygdala (emotion/fear), Hippocampus (memory/learning), Cingulate Cortex (integrating emotional info), and the Ventral Striatum (reward/motivation). The Cerebral Cortex makes up $70-80\%$ of total brain mass. It is divided into four lobes. The Frontal Lobe, located anterior to the central sulcus, includes the motor cortex (planning/execution of movement) and the prefrontal cortex (executive functions, decision making). The Parietal Lobe, posterior to the central sulcus, handles sensory integration. It contains the primary somatosensory cortex (tactile, pain, temperature) and the secondary somatosensory cortex. These are organized somatotopically and contralaterally.

The Occipital Lobe is the most caudal and specializes in vision. Information flows from the retina to the optic nerve, through the optic chiasm (decussation), to the lateral geniculate nucleus of the thalamus, then to the primary visual cortex (striate cortex) and extrastriate cortex. The Temporal Lobe processes auditory information and language. It contains the auditory cortex; signals flow from the cochlea to the medial geniculate nucleus of the thalamus, then to the primary and secondary auditory cortices. Microscopically, the cortex has six layers, featuring pyramidal cells (projection neurons) and stellate cells (interneurons), organized in vertical functional columns. Korbinian Brodmann classified these into the Brodmann areas based on cellular structure.

Cellular Biology and Glial Functions

The nervous system contains neurons, blood vessel cells, stem cells, and glial cells. Glia, once thought to be simple "glue," are now recognized as active participants in brain function. The ratio of glia to neurons is estimated between $1:1$ and $3:1$. Glia provide structural support, nutrition, and chemical regulation. Astrocytes are star-shaped cells that regulate ions and neurotransmitters, form the BEE, and modulate blood flow. They transform glucose into lactate for neuronal energy. Pathologies include Alzheimer's and glioblastoma. Ependymal cells line the ventricles and move LCS with cilia. Microglia act as the brain's immune system, eliminating debris through phagocytosis and participating in synaptic pruning. Overactivation of microglia leads to chronic inflammation.

The myelin sheath, a lipid-rich membrane, insulates axons for faster signaling. In the CNS, oligodendrocytes produce myelin; one cell can myelinate multiple axons. In the PNS, Schwann cells myelinate a single axon and can guide regeneration. Multiple Sclerosis is an autoimmune disease where the immune system attacks CNS oligodendrocytes, replaced by scar tissue (plaques) from astrocytes. Neurons are the basic units of the nervous system, characterized by a soma (metabolic center with nucleus and organelles like mitochondria), dendrites (receiving inputs), and an axon (transmitting signals). Axons originate at the axon hillock (integration cone) and end in terminal buttons. DNA in the nucleus is transcribed to mRNA, which is translated to protein in the cytoplasm.

Spines on dendrites (in spiny neurons like pyramidal cells) are specialized sites for excitatory synapses and are highly dynamic, representing neuroplasticity. Axonal transport involves microtubules and motor proteins: kinesin for anterograde transport (soma to terminal) and dynein for retrograde transport (terminal to soma). Regeneration is limited in the CNS due to glial scarring, but more effective in the PNS guided by the basal lamina.

Electrophysiology and Synaptic Transmission

The resting membrane potential is approx $-70\,mV$, meaning the inside is more negative than the outside. The lipid bilayer prevents ion passage, but ion channels and pumps (like the Sodium-Potassium Pump) maintain the gradient. The pump uses ATP to move $3\,Na^+$ out and $2\,K^+$ in. Ions move based on the electrochemical gradient. Neurons receive graded potentials: Excitatory Postsynaptic Potentials (PPSE) depolarize the membrane, while Inhibitory (PPSI) hyperpolarize it. Integration occurs at the integration cone; if the threshold (approx $-55\,to\,-65\,mV$) is reached, an Action Potential (AP) is triggered.

The AP is an "all-or-nothing" event. Depolarization is caused by the influx of $Na^+$, followed by repolarization/hyperpolarization via $K^+$ efflux. During the absolute refractory period, no new AP can occur; during the relative period, a stronger stimulus is needed. Myelinated axons utilize saltatory conduction, where the AP "jumps" between Nodes of Ranvier, increasing speed and efficiency. Electroencephalography (EEG) records cortical electrical activity non-invasively through frequencies: Delta ($0,1-3,9\,Hz$) for deep sleep, Theta ($4-8\,Hz$) for REM/meditation, Alpha ($-12/14\,Hz$) for relaxed wakefulness, Beta ($14-30\,Hz$) for active thinking, and Gamma ($>40\,Hz$) for concentration. Optogenetics is a local technique using light-sensitive proteins (opsines like Channelrhodopsin for activation or Halorhodopsin for inhibition) to control specific neurons.

Synapses can be electrical (gap junctions allowing direct ion flow via connexons, fast and synchronized) or chemical (separated by a synaptic cleft, requiring neurotransmitters). Chemical transmission involves synthesis, packaging in vesicles, ${Ca}^{2+}$-dependent exocytosis, receptor binding (ionotropic for fast action, metabotropic for slow protein G-coupled action), and termination (reuptake or enzymatic degradation). Volumetric transmission involves neurotransmitters diffusing from axonal varicosities. The tripartite synapse includes the astrocyte's role in neurotransmitter reuptake.

Specific Neurotransmitter Systems

Acetylcholine (ACh) is vital for memory, attention, and muscle contraction. It is synthesized by choline acetyltransferase and degraded by acetylcholinesterase. Receptors are nicotinic (ionotropic, neuromuscular junction) or muscarinic (metabotropic). Toxins like botulinum block release, while sarin gas inhibits degradation irreversibly. Myasthenia gravis involves autoimmune attacks on nicotinic receptors.

Monoamines include Catecholamines (Dopamine, Noradrenaline, Adrenaline) and Indolamines (Serotonin). Serotonin (5-HT), derived from tryptophan, regulates mood, sleep, and appetite. Imbalances are linked to depression and bipolar disorder. Medications like SSRIs block reuptake. Dopamine (DA) regulates movement (nigrostriatal via), reward/motivation (mesocorticolimbic via), and hormones. Deficits cause Parkinson's (treated with L-DOPA); excess DA in the mesolimbic path is linked to schizophrenia's positive symptoms. Noradrenaline (NE) from the locus coeruleus regulates vigilance and stress within the sympathetic nervous system. Histamine acts as a neuromodulator for wakefulness and metabolism.

Glutamate is the primary excitatory neurotransmitter, using AMPA and NMDA receptors ($Mg^{2+}$ block). Excess causes excitotoxicity. GABA is the primary inhibitor. Benzodiazepines enhance GABA's effect to treat anxiety. Non-conventional neurotransmitters include gases like Nitric Oxide (NO), which acts as a retrograde signal for memory, and Endocannabinoids (Anandamide, 2-AG) which regulate mood and appetite via retrograde inhibition. Neuropeptides like Oxytocin (social bonding) and Opioids (Endorphins, Enkephalins) modulate pain and emotion. Exogenous opioids like heroin cause high dependency and risk of fatal respiratory depression in overdose, treatable with naloxone.