Pathways of the basal ganglia

Pathways of the basal ganglia: The basal ganglia receives afferents from, and provides efferents to, the cerebral cortex. Efferents that affect motor activity are organized into two pathways: direct and indirect.

• The direct pathway initiates movement by stimulating the motor cortex through the thalamus.
• The indirect pathway inhibits movement by inhibiting the motor cortex through the thalamus.

Both pathways are driven by excitatory glutamate input from cerebral cortex neurons. Dopamine from the substantia nigra pars compacta promotes movement in two ways:

• Binding to D1 receptors activates the direct pathway.
• Binding to D2 receptors inhibits the indirect pathway.

In the direct pathway, excitatory input from the primary and premotor cortex stimulates substance P-containing GABA neurons in the striatum (mainly the putamen). These striatal neurons release the inhibitory neurotransmitter GABA, which inhibits GABA neurons in the internal segment of the globus pallidus. When the internal globus pallidus neurons are inhibited, they release less GABA onto the VA and VL nuclei of the thalamus. This disinhibits (functionally excites) the VA and VL thalamic nuclei, which then send excitatory output to the motor cortex, initiating movement. In addition, the nigrostriatal pathway (from the substantia nigra to the striatum) releases dopamine, which binds D1 receptors on striatal GABA neurons and further excites the direct pathway.

In the indirect pathway, excitatory glutamate input from the cerebral cortex activates enkephalin-containing GABA neurons in the striatum. These neurons inhibit a second set of GABA neurons in the external segment of the globus pallidus. This disinhibits (activates) the subthalamic nucleus. Excitatory glutamate output from the subthalamic nucleus then excites GABA neurons in the internal segment of the globus pallidus, which increases inhibition of the VA and VL nuclei of the thalamus. This reduces activity in the motor cortex and also suppresses the direct pathway. The indirect pathway is potentiated by cholinergic neurons in the striatum. Dopamine released by the nigrostriatal pathway binds to D2 receptors and inhibits the enkephalin-containing GABA neurons of the indirect pathway.

Reticular activating system or RAS: The RAS is a network of neurons in the brainstem that projects to the cerebral cortex through the thalamus and hypothalamus to regulate arousal and wakefulness. Ascending fibers are part of the ascending reticular system, while fibers descending from the reticular nuclei to the spinal cord form the reticulospinal tract. RAS lesions may lead to sleep disturbances such as narcolepsy and hypersomnia. In PTSD (post-traumatic stress disorder), the RAS is hyperactive. The reticulospinal tract is involved in maintaining tone, balance, and posture. The RAS is made up of three specific nuclei as follows:

1. Locus coeruleus nucleus with norepinephrine-containing neurons. It is most active during waking and slow wave sleep.

2. Dorsal raphe nucleus with serotonin-containing neurons. It is most active during waking and slow wave sleep.

3. Pedunculopontine nucleus with acetylcholine- and glutamate-containing neurons. This nucleus is most related to arousal states of waking and REM sleep.

Sleep physiology: Sleep consists of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM occurs first, followed by REM sleep, in a cyclical pattern every 90 minutes until a person awakens. With each successive cycle, the amount of sleep spent in NREM decreases and REM increases.

NREM sleep: In an awake person with eyes open, beta waves are seen on EEG. Beta waves are high-frequency, low-voltage waves. When eyes are closed, the dominant EEG waves are alpha waves, which have comparatively higher voltage. NREM sleep is induced by GABA neurons in the preoptic area of the hypothalamus and serotonin-secreting raphe nuclei. NREM sleep has four stages (I to IV):

• Stage I: lower-frequency theta waves
• Stage II: short bursts of high frequency called sleep spindles and large K complexes
  • Sleep spindles result from periodic interactions between thalamic and cortical neurons.
• Stages III and IV: slow, high-voltage delta waves
  • Stage IV is also called deep sleep.

In NREM sleep, skeletal muscles are relaxed but maintain tone, and blood pressure and heart rate decrease.

REM sleep: REM sleep is also called paradoxical sleep because the EEG resembles that of an awake person. The EEG reverts from synchronized to desynchronized activity, and “sawtooth” waves may be seen. REM sleep is induced by cholinergic neurons in the ascending arousal system in the brainstem. REM is characterized by rapid, saccadic eye movements, loss of muscle tone, constriction of pupils, penile and clitoral tumescence, and fluctuations in heart rate, blood pressure, and respirations. Norepinephrine- and serotonin-secreting neurons end REM sleep and help transition back to NREM sleep.

Newborns spend 50% of sleep in REM, young adults 25%, while elderly individuals spend little time in REM sleep. With aging, total sleep time decreases, time spent in both REM and NREM decreases, awakenings become more frequent, and stage IV sleep is reduced.

CSF: Compared to blood, CSF has similar concentrations of sodium, chloride, bicarbonate ion, and osmolarity. It has lower concentrations of potassium, calcium, glucose, and amino acids, and higher levels of magnesium and creatinine. CSF pH is lower than blood. Cholesterol and proteins cannot normally enter the CSF due to their larger size, although amino acids are present.