Subcortical Neuroanatomy Brad Cole, MD

Three subcortical structures will be discussed in this lecture: • Diencephalon • Basal ganglia • White matter

Diencephalon

1. Thalamus We have previously outlined the anatomical boundaries of the diencephalon, which are located between the mesencephalon and the telencephalon. Recall that there are two important anatomical landmarks that help define the thalamus on horizontal sections: • Medial thalamic border: The third ventricle • Lateral thalamic border: The posterior limb and genu of the internal capsule

The thalamus is a massive collection of neuronal cell groups which function as the main processing center for information traveling to the from all ascending sensory pathways (except those related to olfaction) as well as from other CNS structures. The thalamus then processes this information and relays only the “important” information to the cortex. For this reason, the thalamus is sometimes called the “executive secretary” or the “gateway” to the cerebral cortex. These connections between the cerebral cortex and the thalamus are reciprocal (i.e. – x thalamic nuclei “talks” to x cortical area, x cortical area “talks” back to x thalamic nuclei, etc.).

The external medullary lamina covers the lateral aspect of the thalamus. This represents myelinated fibers that are entering or leaving the thalamus.

The internal medullary lamina also consists of myelinated fibers and extends into the substance of the thalamus where it forms partitions or boundaries that divide the thalamus into principle cell groups: anterior, medial, lateral, and intralaminar nuclear groups (the latter are located within the internal medullary lamina).

A. Anterior Thalamic Nuclei (ATN)

The ATN is the most rostral thalamic nuclei and is located caudolateral to the interventricular foramen of Monroe. The ATN receives mainly limbic projections from the mammillary bodies via the mammillothalamic tract. The hippocampus also projects to the ATN via fibers that leave the fornix. Output of the ATN travels through the anterior limb of the internal capsule and is primarily to the cingulate gyrus as part of Papez circuit.

B. Medial Thalamic Nuclei (Dorsomedial Nucleus – DM)

This nucleus relays information from the amygdala to large parts of the frontal lobes, mainly the prefrontal cortex.

The ATN and DM together are considered as the limbic thalamic nuclei because of their extensive connections with limbic structures and the cerebral cortex. Both nuclei are important in memory formation and in motivational behavior.

C. Lateral Thalamic Nuclei

1. Dorsal nuclear groups

(a) Pulvinar and Lateral Posterior (LP) Nuclei – the Pulvinar and the LP nuclei are together considered as a single functional entity. Input is from the superior colliculus and with projections to the visual association cortex. This extra-geniculate visual pathway is important in visually guided pursuit movements and in object localization.

2. Ventral nuclear groups

(a) Ventral Anterior (VA) – the principle basal ganglia afferent nucleus, receiving fibers from the output nucleus of the thalamus (the internal segment of the globus pallidus and the pars reticulate of the substantia nigra). The VA relays this information to widespread areas of the frontal lobe premotor cortex, allowing the basal ganglia to assume its important role in motor function.

(b) Ventral Lateral (VL) – receives some inputs from the basal ganglia but mainly receives afferents from the cerebellar nuclei. Information then projects to the frontal lobe primary motor cortex, allowing the cerebellum to inform the cerebral cortex about the accuracy of the intended movement.

(c) Ventral Posterior Lateral (VPL) – conveys somatosensory information from the contralateral extremities (medial lemniscus and STT). Output is to the postcentral gyrus (primary sensory cortex).

(d) Ventral Posterior Medial (VPM) – conveys the same somatosensory information as the VPL, except from the contralateral face. The VPM also relays gustatory information from the nucleus solitarius. VPM fibers project to the postcentral gyrus.

The pathway from the trigeminal nuclei to the thalamus is called the trigeminal lemniscus (aka, the trigeminothalalmic tract). Recall that pain and temperature for the extremities synapses in the substantia gelatinosa after ascending in Lissauer’s tract. In the brain stem, the spinal trigeminal nucleus and tract is merely the rostral continuation of these areas in the and also cross over:

The most common clinical manifestation of a lesion to the thalamus is severe impairment of somatic sensations on the contralateral side of the body (face, arm, and leg). An ischemic in the thalamus is usually due to occlusion of the thalamogeniculate artery which is a branch of the posterior cerebral artery. The VPL and VPM are the thalamic nuclei involved in this syndrome. In addition to sensory loss, severe pain of the contralateral face, arm and leg, can be a chronic complication. This is referred to as the thalamic pain syndrome or Dejerine-Roussy syndrome.

(e) Ventral Posterior Inferior (VPI) – receives vestibular input with projection to the postcentral gyrus

D. Geniculate Thalamic Nuclei

(a) Lateral Geniculate Body (LGB) – the thalamic center for processing visual information. The LGB receives visual input via the optic tract (from the ipsilateral temporal retina and from the contralateral nasal retina) and then projects to the primary visual cortex via the optic radiations. A point-to-point map the visual space is maintained in the LGB.

(b) Medial Geniculate Body (MGB) – the thalamic center for processing auditory information. It receives this information from the inferior colliculus and projects to the primary auditory cortex in the gyrus of Heschl (on the superior temporal gyrus).

E. Thalamic Nuclei within the External and Internal Medullary Lamina

(a) Clusters of neurons called the thalamic reticular nuclei are located with the external medullary lamina. These nuclei are GABAergic (inhibitory). All corticothalamic and thalamocortical fibers pass through this area on their way to or from the thalamus. In this way, the thalamic reticular neurons are able to control the flow of information traveling between the thalamus and cortex. The thalamic reticular nucleus is the only thalamic nucleus that does not project to the cerebral cortex.

(b) Embedded within the internal medullary lamina are a discontinuous group of neurons that form the intralaminar nuclei. The most important of the intralaminal nuclei is the centromedian nuclei (CM). The CM has important connections with the reticular formation and the basal ganglia:

• Input is received from ascending slow pain pathways (spinoreticular tract → reticular formation → CM) and project to wide areas of the somatosensory cortex. This pathway may be important in the regulation of pain tolerance.

• Input from the reticular formation in the brain stem projects to widespread non- specific areas of the cerebral cortex. These fibers exert a general effect on the overall excitability of cortical neurons and are regarded as part of an “ascending activating system” that regulates the mechanisms of cortical arousal. If these reticular fibers do not reach the cortex, coma will ensue.

The diffuse, non-specific cortical projections of the intralaminar nuclei are in contrast to the VLP, VPM, MGB and LBG, for example, which all maintain a precise point-to-point transfer of information.

• Along with the VA and VL, the CM is also part of the basal ganglia circuitry. It receives output from the GPi and SNpr (the basal ganglia output nuclei), but instead of projecting to the cortex, output is to the striatum. This, the CM participates in motor control mechanism.

A summary of thalamic nuclei according to function:

Input Nucleus Output

1. Sensory relay nuclei Somatosensory VPL Primary sensory cortex (medial portion) Facial sensory/ taste VPM Primary sensory cortex (lateral portion) Vision: Retina LGB Primary visual cortex Superior Colliculus Pulvinar, LP Associative visual cortex Auditory MGB Primary auditory cortex

2. Motor relay nuclei Basal Ganglia VA>> VL Premotor, Primary motor cortex CM Striatum (Basal Ganglia) Cerebellum VL Primary motor cortex

3. Limbic relay nuclei Mammillary bodies ATN Cingulate cortex Amygdala DM Prefrontal cortex

4. Non-specific cortex relay nuclei Slow pain CM Non-specific areas of cortex

2. Subthalamus

The is an important relay nucleus in the basal ganglia circuitry and will be discussed with the basal ganglia below.

3. Epithalamus

The epithalamus consists of the pineal gland and the habenular nuclei:

1. Pineal gland – We have previously considered some aspects of the pineal gland, melatonin production and circadian rhythms. Pinealomas (pineal gland tumors) can cause Parinaud’s syndrome discussed earlier.

4. Hypothalamus

Covered in a separate lecture by Dr. Kirby

White matter

Recall that there are three types of white matter fibers: projection, association, and commissural. The centrum semiovale is near the cortical neurons and refers to areas of the white matter that contain all three fiber types. In this lecture, we will only review the internal capsule, since we have now discussed all of the pathways that travel through this clinically important subcortical area.

The posterior limb contains ascending sensory fibers traveling from the extremities to the cortex via the thalamus (thalamocortical or superior thalamic radiations), as well as the descending motor fibers going from the motor cortex to the spinal cord (corticospinal tract, CST). The sensory fibers are supplied by the thalamogeniculate arteries, which are a branch of the posterior cerebral artery. The genu contains the (CBT), which are descending motor fibers from the motor cortex that supply the brain stem. Both the CST and the CBT are supplied by the lenticulostriate artery. There is also overlapping blood supply to the entire posterior limb of the internal capsule by the anterior choroidal artery.

The anterior limb contains most of the corticopontocerebellar tract, the anterior thalamic radiations (which is the part of Papez circuit that connects the anterior nucleus of the thalamus to the cingulate gyrus) and the frontal eye fields which are important for saccadic eye movements.

The nearby optic radiations convey visual information from the thalamus (lateral geniculate nucleus) to the striate cortex.

Clinical aspects: • The most common small vessel stroke syndrome is the pure motor stroke which results in hemiparesis of the contralateral face, arm and leg. The blood vessel involved is the lenticulostriate artery which supplies the CST and the CBT.

• A pure sensory stroke results from a stroke involving the VPL and VPM in the thalamus (less likely involving the ascending sensory fibers in the posterior limb of the internal capsule). Patients have a loss of sensation in the contralateral side of the body. The blood vessel involved is the thalamogeniculate artery.

• An isolated lesion of the genu of the internal capsule results in contralateral lower facial weakness (corticobulbar tract).

• Multiple subcortical that destroy a large percentage of the corticobulbar tract results in a condition known as pseudobulbar palsy which is caused by a disconnect between the cortex and the brain stem. Patients have:

- and (loss of innervation to nucleus ambiguous and hypoglossal nucleus) - emotional incontinence - (due to the large number of strokes which impairs cognitive function) - although not classified as part of pseudobulbar palsy, most patients will also have hemiplegia and other focal findings on exam from the multiple strokes

• is the most common disease of the cerebral white matter and occurs in young adults, typically as a relapsing-remitting form with episodes of demyelination that then recover. Men in their 40's and early 50's are more likely to develop a primary progressive form. Multiple sclerosis also involves the optic nerve and spinal cord since these are CNS structures and myelinated by oligodendrocytes.

• Apraxia refers to a failure in the execution of a learned motor task despite normal strength, coordination, and sensation. There are many causes of apraxia. Patients have difficulty with any motor activity such as dressing, eating, or using the TV remote control but not because of weakness, ataxia, sensory, or visual loss. On exam, patients with apraxia have difficulty showing how they would flip a coin, salute, or brush their teeth. A lesion of the anterior corpus callosum causes left hand apraxia. Imagine asking a patient to imitate how to flip a coin or to salute with the right hand. The command is understood in Wernicke’s area and then moves forward to the left motor cortex resulting in no difficulty doing this with the right hand. When asked to do this with the left hand, however, the “motor program” from the left hemisphere cannot cross over to the right motor cortex. Thus, the left hand is strong and has normal sensation, but cannot accurately perform motor tasks.

Basal Ganglia:

The basal ganglia are deeply located neuronal masses that are derived from the telencephalon (caudate, putamen, and globus pallidus), diencephalon (subthalamic nucleus), and mesencephalon (substantia nigra). These nuclei are intimately interconnected and communicate using a multitude of different neurotransmitters. The knowledge of these interconnections and the neurotransmitters used is clinically relevant in terms of understanding the pathophysiology and treatment of movement disorders. Diseases or lesions that involve the basal ganglia are called “movement disorders” since abnormalities of movement are the primary feature. Unlike diseases or lesions of the upper or lower motor neurons however, patients with movement disorders are not generally weak, but rather have difficulties with motor control ranging from excessive involuntary movements (such as and ) to a relative poverty of movement (bradykinesia). The basal ganglia also contribute to higher mental functions although this is poorly understood.

The cortex communicates with the basal ganglia via the striatum (caudate and putamen). This information is processed by the basal ganglia and then output is directed back to the motor cortex (not to the brain stem or spinal cord nuclei) via the thalamus. Although much is known about the internal connections of the basal ganglia, little is known about the actual nature of the information processing.

Striatum - the striatum consists of the caudate and putamen. It receives afferents from the motor cortex, more widespread cortical areas, the substantia nigra (pars compacta), and the centromedian nucleus (CM) of the thalamus. The striatum is more than just a relay center since a substantial amount of information processing occurs. Local processing within the striatum involves interneurons that use acetylcholine as the primary neurotransmitter. Output from the striatum is to the internal segment of the globus pallidus and substantia nigra pars reticulata (using GABA and substance P) and to the external segment of the globus pallidus (using GABA and enkephalin). Inputs to the striatum from the substantia nigra pars compacta use dopamine which binds to dopamine receptors in the striatum. The D1 receptor is stimulated by dopamine. This occurs by activating adenyl cyclase which leads to an increased intracellular level of cAMP. The D2 receptor is inhibited by dopamine, which inhibits adenyl cyclase activity.

Globus Pallidus - The internal segment of the globus pallidus receives afferents from the striatum (GABA and substance P) as well as from the subthalamic nucleus (glutamate). The internal segment of the globus pallidus as well as the substantia nigra (pars reticulata) is the primary output nucleus of the basal ganglia sending information back to the thalamus (VA > VL) and eventually the cortex. The external segment of the globus pallidus receives afferents from the striatum (GABA and enkephalin) and projects to the subthalamic nucleus (GABA).

Efferents from striatum to the internal segment of the globus pallidus and the substantia nigra (pars reticulata) are called the “direct” pathway since it is the most direct route to the output nuclei. Efferents from the striatum to the external segment of the globus pallidus are called the “indirect” route since the information first travels through the subthalamic nucleus prior to arriving in the output nuclei (the internal segment of the globus pallidus and the substantia nigra – pars reticulata).

Parkinson’s disease (PD) is due to degeneration of the dopamine producing neurons in the substantia nigra – pars compacta. The basic premise of correlating the basal ganglia wiring diagram with PD is that decreased production of dopamine leads to reduced glutamate stimulation of the motor cortex. Thus, the patient “slows down” and has difficulty moving with a .

Hemiballismus is most often caused by a stroke in the contralateral subthalamic nucleus. Notice that in this case there is now glutamate overstimulation of the motor cortex.