In order to recognize pathology, it is necessary to know what normal tissues look like. To that end, we present here a set of slides which depict normal anatomy, both on the gross and microscopic level. Throughout this course, whenever new pathologic concepts are presented, we will also strive to present corresponding normal tissues for comparison. Click any of the thumbnails below to enlarge an image, or any of the links for further details and images on a subtopic.

The dura mater consists of two layers of dense collagen encompassing the cranial cavity and enclosing the venous sinuses. Its outer layer, apposed to bone, forms the cranial periosteum, whereas the inner layer overlies the cortical surface lined by arachnoid. Numerous pathologic processes may involve the dura or its adjacent spaces, including infection, neoplasia, and hemorrhage. A common symptom of dural pathology is headache. The meninges are found at the surface of the brain. The arachnoid or leptomeninges form a spider web-like covering of the brain and spinal cord. The pia mater is tightly applied to the surface of the brain although it may be artefactually separated from the underlying tissue. The subarachnoid space, which contains the cerebrospinal fluid and meningeal blood vessels, separates the pia from the overlying arachnoid membrane. The arachnoid is lined by meningothelial cells. Meningiomas arise from these cells, and the microscopic features of these neoplasms recapitulate their normal syncytial appearance. Other pathologic processes that commonly involve the leptomeninges or subarachnoid region include meningitis of all types, hemorrhage (particularly from head trauma or ruptured saccular aneurysm), metastatic carcinoma (carcinomatous meningitis or meningeal carcinomatosis) and, less commonly, spread of primary brain tumors.

The cerebral hemispheres are divided into four lobes (frontal, parietal, temporal and occipital) and further separated into raised areas (gyri) and furrows (sulci). Regions of the cerebral cortex have been subdivided in a variety of ways both morphologically and functionally. Perhaps the best-known cortical map was that developed in 1909 by Korbinian Brodmann. Microscopically, however, most regions of cortex are not readily distinguishable from one another on routine histochemical staining. Therefore, when sectioning autopsy brains, neuropathologists often plan their cortical sections to include features for purposes of localization. For example, a section of insular cortex might include adjacent basal ganglia; a section of cingulate cortex might include the corpus callosum. Two areas with distinctive histology are the motor cortex and the primary visual cortex. The motor cortex, located in the precentral gyrus of the frontal lobe, displays giant pyramidal neurons (“Betz cells”) in layer 5, that give rise to the efferent corticospinal tract. The primary visual cortex (area 17) demonstrates a radially oriented band of myelinated fibers (external line of Ballinger) that usually visible grossly, known as the line of Gennari. In the relatively thin (~6 micron) H&E stained sections usually used for diagnosis, cortical lamina or neuronal cell layers will not be readily apparent. Cell nuclei, neuronal cell cytoplasm, and apical dendrites of many neurons will be visible on H&E stained sections; however, to fully appreciate neuronal processes (“neurites” = axons and dendrites), special stains are necessary. Neurons often contain distinct cytoplasmic basophilic clumps corresponding to Nissl substance (rough endoplasmic reticulum). Finely granular golden-brown lipofuscin pigment accumulates with age. Satellite glia (astrocytes, oligodendroglia and microglia), often surround neuronal cell bodies. The pink background seen on H&E stained sections known as the neuropil is composed of a rich complex of processes derived from neurons, glia, and other elements.

To demonstrate components of the cortex and white matter, a variety of special stains are used.

Commonly employed histochemical stains include silver-based stains (e.g. Bielschowsky, Bodian) to highlight axons, neurofibrillary tangles and neuritic plaques; and myelin stains (e.g. Luxol fast blue) for myelin sheaths. More recently, a vast array of immunohistochemical stains has been employed, particularly in the evaluation of the brains from patients with neurodegenerative diseases.

The hippocampus includes the fascia dentata (FD) or “dentate gyrus”, composed of small tightly packed neurons, and the layer of large pyramidal cell neurons which comprise Ammon’s horn. This latter is divided into 4 segments, CA (cornu ammonis) 1 - 4. The FD is composed of a cellular arc of small neurons surrounding the end folium ("endplate") of the pyramidal cell layer, also known as CA4. CA1 and 2 form the medial floor of the temporal horn of the lateral ventricle; CA2 is usually more compact than CA1.

Pathological changes vary somewhat by region, with the most common associated with global ischemia. CA1 (Sommer sector), also known as the "susceptible sector" is the most vulnerable segment to ischemia, followed by CA4, while sector CA2 (also known as the "resistant" sector), sector CA3 and the FD are relatively resistant. With an acute ischemic insult, susceptible neurons undergo acute ischemic cell change, consisting of nuclear pyknosis and cytoplasmic hypereosinophilia ("eosinophilic neuronal degeneration). This change requires a delay of at least 6 hours following the insult to be apparent; the hippocampus of a patient who dies quickly may show no histologic alterations. With chronic ischemic injury, neuronal loss and gliosis result. Brief ischemic episodes (~5 minutes) may lead to changes only in CA1, however, without affecting other brain areas. More severe ischemia may lead to the loss of all hippocampal pyramidal cells bilaterally and may be associated with amnesia. Hypoglycemia causes a similar pattern of pathology to ischemia, although some authors have suggested minor differences in distribution, particularly degeneration in the FD.

The subcortical white matter includes the immediate subcortical, radially oriented U fibers. Deeper white matter consists of myelinated fibers with adjacent oligodendroglia oriented in linear fashion, accompanied by astrocytes, microglia and blood vessels. Disorders of myelin fall into two major categories: demyelinating diseases, in which there is preferential damage to normally formed white matter, and dysmyelinating disorders, in which myelin is malformed. A variety of processes, including immune-mediated demyelination (e.g., multiple sclerosis), neoplastic, toxic, and infectious disorders may selectively involve white matter.

The basal ganglia include the caudate and putamen (corpus striatum), the globus pallidus (GP), and the claustrum. The caudate and putamen, readily identified by the white matter bundles (striae) within them, have a similar histologic appearance characterized by both small and large neurons, with a ratio of polymorphic small (<15 microns) to multipolar large (>40 microns) cells of approximately 160:1. The external medullary lamina separates the putamen from the GP. The internal medullary lamina divides the GP into the medial pars interna and the lateral pars externa. The GP is comprised of a meshwork of dense myelin fibers (that imparts the pale appearance of the pallidum) with embedded large neurons. This fiber density reflects the role of the GP as the major outflow system for the basal ganglia. The internal capsule separates the caudate from the putamen and GP (together known as the "lenticular nucleus"), whereas the external capsule separates the putamen from the claustrum. The extreme capsule lies between the claustrum and the insular cortex. The basal ganglia and thalamus are concerned with coordination of motor and sensory modalities.

The brainstem regulates primitive functions as breathing, heart rate, swallowing, reflexes, and arousal; the real estate in the brainstem is quite valuable, with relatively small lesions often resulting in devastating deficits. The midbrain, located between the diencephalon (thalamus) and the pons, plays a key role in the control of eye movements and visual and auditory functions. It contains the largest pigmented nucleus in the brain, the substantia nigra, which lies just superior to the cerebral peduncles. The midbrain tectum contains the colliculi and the aqueduct of Sylvius. Tumors of the pineal region may deform the corpora quadragemini (superior and inferior colliculi) and cerebral aqueduct, resulting in hydrocephalus and paralysis of upward gaze.The substantia nigra (SN) appears grossly as a linear zone of black pigment, due to the presence of neuromelanin within neurons. This dark zone (pars compacta) contains dopaminergic neurons projecting to the corpus striatum of the basal ganglia. Ventral to the compacta is the pars reticulata, where neurons are less densely packed and non-pigmented.

The cerebellar cortex is composed of an external molecular layer, a single layer of large pyramidal neurons (Purkinje cells) and a densely cellular internal granular neuronal cell layer. In infants less than one year old, a superficial external granular cell layer overlies the molecular layer. The Purkinje cells are large, flask-shaped neurons with apical dendrites oriented in the molecular layer. Within the deep cerebellar white matter, the dentate nucleus is the most recognizable structure and is composed of large, slightly hypereosinophilic neurons. The cerebellum coordinates voluntary movement, as well as balance and equilibrium, and provides some memory for reflex motor acts. Damage may result in impaired coordination, intention tremor, vertigo, and slurred/ scanning speech. A variety of neoplasms may involve the cerebellum, particularly the pilocytic astrocytoma and medulloblastoma in childhood. Global ischemia preferentially affects the cerebellum. Purkinje cells, particularly in the depths of folia, are exquisitely sensitive to ischemic insults. When Purkinje cells are lost, the cells are replaced by the proliferation of adjacent astrocytes (Bergmann gliosis).

The spinal cord also can be involved by the gamut of pathological processes, most commonly neoplasms, degenerative disorders (e.g. motor neuron disease), and demyelinating disease (e.g. multiple sclerosis).

Further reading

Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics. 2007 Mar-Apr;27(2):525-51.

J. Thammaroj, C. Santosh and J.J. Bhattacharya. The hippocampus: modern imaging of its anatomy and pathology. Practical Neurology Volume 5 Issue 3, Pages 150 - 159

DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007 Jan;64(1):20-4.