Clinical Neuroscience Week 9 - Basal Ganglia

• The diencephalon consists of the thalamus, hypothalamus, subthalamus, and epithalamus.

Thalamus

• The thalamus is the largest part of the diencephalon (80%) and helps the brain prioritize attention.
• It filters and integrates sensory information before relaying it to the cortex.
• Serves as a relay station for incoming motor and sensory information (except smell).
• Blood supply comes from the posterior cerebral artery, posterior communicating artery, and basilar communicating artery.
• Egg-shaped structure above the brainstem, with two halves connected by the interthalamic adhesion.
• Integrates sensory information, regulates motor activity and consciousness, and contributes to sleep, wakefulness, learning, memory, and perception.
• Composed of various nuclei made of excitatory neurons projecting in an organized way to the cortex.
• The intramedullary lamina, a y-shaped white matter sheet, divides the thalamus into three cell groups: anterior, medial dorsal, and lateral.
• Has both afferent and efferent connections.
• The reticular nucleus (RN) is a sheet covering the thalamus that influences other nuclei.
• Four functional groups of thalamic nuclei: relay, association, nonspecific, and reticular.

Functional Groups of Thalamic Nuclei

• Relay nuclei transmit specific sensory information to related cortical areas.
• Association nuclei integrate information from multiple sources for higher-order processing.
• Nonspecific nuclei are involved in arousal and attention.
• Reticular nuclei regulate thalamic activity.

Relay Nuclei

• Anterior Nucleus: Receives input from the mammillothalamic tract, cingulate cortex, and hippocampus; projects to the prefrontal and cingulate cortex.
• Ventral Anterior (VA) Nucleus: Afferents from substantia nigra (pars reticulata) and globus pallidus internus (GPi); efferents to prefrontal cortex and frontal eye field.
• Ventral Lateral (VL) Nucleus (anterior part): Receives input from the globus pallidus (internal segment) and cerebellum; projects to the supplementary motor area.
• Ventral Lateral (VL) Nucleus (posterior part): Afferents from deep cerebellar nuclei; efferents to motor/pre-motor association cortex.
• Ventral Posterolateral (VPL) Nucleus: Receives input from the medial lemniscus/spinothalamic tract (body) and vestibular pathways; projects to the somatosensory and vestibular cortex.
• Ventral Posteromedial (VPM) Nucleus: Afferents from the medial lemniscus/spinothalamic tract (head); efferents to the somatosensory cortex (parietal association cortex).
• Medial Geniculate Nucleus: Receives input from the inferior colliculus; projects to the primary auditory cortex.
• Lateral Geniculate Nucleus: Afferents from the optic tract; efferents to the primary visual cortex.

Association Nuclei

• Lateral Dorsal (LD) Nucleus: Receives input from the pretectum, cingulate cortex, hippocampus, and other thalamic nuclei; projects to the cingulate cortex.
• Mediodorsal (MD) Nucleus: Afferents from prefrontal cortex (olfactory), amygdala, striatum, superior colliculus, and other thalamic nuclei; efferents to prefrontal and cingulate cortex, and frontal eye fields.
• Lateral Posterior (LP)/Pulvinar Complex (PUL): Receives input from other thalamic nuclei and nuclei of the superior colliculus; projects to the parietal (LP) and occipital cortex (PUL).

Non-Specific Nuclei

• Intralaminar Nuclei (centromedian, parafascicular, others): Afferents from spinothalamic tract, reticular formation, neuromodulatory system, and amygdala; efferents to widespread areas of the cortex and basal ganglia.
• Midline Nuclei: Receives input from the reticular formation, neuromodulatory system, and amygdala; projects to the cingulate cortex, hippocampus, and corpus striatum.

Reticular Nuclei

• Reticular Nucleus (RN): Receives input from the cortex, underlying thalamic nuclei, and reticular formation; projects to underlying thalamic nuclei.
• All thalamic nuclei, except the reticular nucleus, have reciprocal excitatory connections with the cerebral cortex.
• Sensory inputs are excitatory, and most neurons in the thalamic nuclei are glutamatergic.
• Reticular nucleus inhibits activity of other thalamic nuclei and does not directly excite the cerebral cortex, acting as a gatekeeper via GABAergic interneurons.
• Relay nuclei transmit specific sensory information to different areas of the cortex, projecting back to association areas.
  • Examples: lateral geniculate for vision, medial geniculate for auditory, and ventral posterior lateral nuclei for somatosensory information.
• Non-specific nuclei send diffuse projections to large regions of the cortex, involved in arousal and attention rather than specific sensory data.

Ventral Lateral (VL) Nucleus

• Central hub for motor control.
• Receives signals from the cerebellum (movement errors) and basal ganglia (movement initiation).
• Projects heavily to the primary motor cortex (frontal lobe), premotor, and supplementary motor cortices.
• Anterior part (VLa) controls proximal muscles, while the posterior part (VLp) controls distal muscles.
• Lesions can cause ataxia or tremors.
• Target for deep brain stimulation in Parkinson's disease treatment.

Ventral Posterolateral (VPL) vs. Ventral Posteromedial (VPM) Nuclei

• VPL receives somatosensory input from the body (trunk and limbs) via the dorsal column medial lemniscus (DCML) and spinothalamic tract, projecting to the primary somatosensory cortex.
• VPM receives somatosensory input from the head (face and head) via the trigeminal nerve (CN V), projecting to the primary somatosensory cortex.
• Damage to VPM can impair facial sensation contralaterally, affecting touch, pain, and temperature.

Medial Geniculate (MGN) vs. Lateral Geniculate (LGN) Nuclei

• MGN is the primary auditory relay station, receiving signals from the inferior colliculus and projecting to the auditory cortex (temporal lobe).
• LGN is the primary visual relay station, receiving input from the optic tract and projecting to the primary visual cortex (occipital lobe).

Thalamic Reticular Nucleus (TRN)

• Acts as a gatekeeper, inhibiting activity of other thalamic nuclei.
• Regulates sensory information flow to the cortex.
• Plays a key role in attention, arousal, and sensory processing.
• Anterior nucleus is connected to the hippocampus and involved in memory.
• Dorsomedial nucleus is involved in emotional behavior and memory.
• Ventral anterior (VA) and ventrolateral (VL) nuclei are involved in motor functions.
• Ventral Posterolateral (VPL) and Ventral Posteromedial (VPM) Nuclei relay information to the somatosensory cortex.
• Lateral Posterior (Posterolateral) Nucleus integrates sensory input.
• Medial Geniculate Nucleus relays information to the auditory cortex.
• Lateral Geniculate Nucleus relays information to the visual cortex.
• Pulvinar Nucleus processes visual stimuli.

Clinical Implications of Thalamic Damage

• Thalamic Stroke: Can result in weakness, vision changes, speech difficulties, balance problems, pain, sensory and cognitive changes, mood changes, and sleep disturbances.
• Thalamic Pain Syndrome: Chronic pain resulting from thalamic injury, causing spontaneous contralateral pain.
• Symptoms include burning, constrictive pain, allodynia, hyperalgesia, paresthesia, and temperature changes.

Hypothalamus

• Sits below the thalamus and above the pituitary gland, linking the endocrine and nervous systems.
• Maintains homeostasis by influencing the autonomic nervous system and managing hormones.
• Regulates heart rate, blood pressure, and body temperature, and releases hormones that direct other glands.
• Smart control, manages body temperature, blood pressure, hunger/thirst, mood, sleep, and sex drive.
• Produces dopamine (pleasure and coordinated movements) and somatostatin (regulates body functions).
• Anterior pituitary releases hormones (GHRH, GnRH, CRH, TRH) regulated by the hypothalamus; posterior pituitary releases oxytocin and vasopressin.

Clinical Implications of Hypothalamic Dysfunction

• Hypothalamic-pituitary disorders: Hypopituitarism, diabetes insipidus, Prader-Willi syndrome, Kallmann syndrome, acromegaly/gigantism, SIADH, central hypothyroidism, functional hypothalamic amenorrhea, hyperprolactinemia.
• Signs and Symptoms: HTN or hypotension, water retention or dehydration, weight changes, infertility, poor bone health, delayed puberty, muscle loss, temperature fluctuations, insomnia, frequent urination.
• Causes: Head injuries, brain infections/tumors, brain surgery, radiation, birth defects, inflammatory diseases (MS, neurosarcoidosis).

Subthalamus

• Small region below the thalamus that regulates movement via the basal ganglia.
• Fine-tunes voluntary muscle movements.
• Main structure is the subthalamic nucleus.
• Dysfunction can result in motor dysfunction seen in Parkinson's disease.
• Hemiballismus presents with sudden, violent involuntary movements on one side of the body.

Epithalamus

• Smallest, oldest, and most dorsal part of the diencephalon, posterior to the thalamus.
• Connects the limbic system.
• Includes:
  • Pineal Gland: Secretes melatonin to control the sleep-wake cycle.
  • Habenular Nuclei: Receives forebrain afferents and projects to the midbrain, regulating emotions/behaviors.
  • Stria Medullaris: Connects the habenular nuclei with other brain regions (limbic system).

Limbic System

• Known as the emotional brain, initiating need-directed motor activity for survival.
• Manages emotions, behaviors, motivations, memory, and the autonomic nervous system.
• Vital for motivation, learning, and spatial memory.
• Components include the amygdala, hippocampus, hypothalamus, thalamus, and cingulate gyrus.
• Limbic lobe includes the orbital frontal cortex, cingulate gyrus, parahippocampal gyrus, and uncus. Other structures include the temporal pole, hypothalamus, reticular formation, and nucleus accumbens connecting to the limbic system.
• Amygdala:
  • Emotional center for fear, anger, and pleasure.
  • Responds to emotional stimuli, forming emotional memories.
  • Evaluates emotional significance and helps with decision-making.
• Hippocampus:
  • Essential for forming new memories, linking emotions and senses.
  • Consolidates short-term memories to long-term storage and involved in spatial navigation.
• Hypothalamus:
  • Regulates bodily functions like hunger, sleep, and body temperature through hormone regulation.
  • Controls the release of hormones.
• Thalamus:
  • Relay station directing sensory and motor signals to the cerebral cortex.
  • Regulates consciousness, sleep, and alertness.
• Cingulate Gyrus:
  • Interprets situations, guides appropriate behaviors, and role in empathy & social interactions.
• Nucleus Accumbens:
  • Processing rewarding experiences, motivation, and translating emotional responses to motor activity.
  • Key component of the brain’s pleasure center.
• Damage to the limbic system: Can result in anxiety, addiction, obsessive compulsive disorder, depression, and post-traumatic stress disorder.

MOVE - Limbic Network Function

• M = Memory and Motivation: Memory involves attention, retrieval, and declarative learning. Motivation involves the desire to learn.
• O = Olfaction: Only sensory system that does not have to go through the thalamus as a second-order synapse.
• V = Visceral: Drive includes thirst, hunger, temperature regulation, and endocrine functions, including sympathetic and parasympathetic reactions.
• E = Emotion: Affects self-concept, worth, emotional body image, tonal responses of the motor system, attitude, personality.

Basal Ganglia - Components

• Consists of the striatum, globus pallidus, subthalamic nucleus, and substantia nigra.
• Striatum includes the caudate nucleus, putamen, and nucleus accumbens.
• Globus pallidus includes the external (GPe) and internal (GPi) segments.
• GPe, GPi, and putamen form the lentiform nucleus.
• Regulates voluntary movement, filters motor signals, and learns new motor skills.
• Integrates information from various areas of the brain to control movement, cognition, and emotion.
• Acts as a gatekeeper for movement initiation.
• Influences cognitive functioning, decision making, reward processing, and learning.
• Information flows from the cerebral cortex to the basal ganglia and back to the cortex via the thalamus.
• Controls cortical activity through the thalamus.
• The structures are interconnected with the limbic system.
• Best known for motor control but critical for emotion & behavioral inhibition.
• Damage to the basal ganglia: Can result in movement disorders such as Parkinson's disease or Huntington’s disease.

Basal Ganglia - Striatum

• Caudate Nucleus: C-shaped structure that receives input from the cortex; sends signals to the thalamus.
• Putamen: Receives input from sensory areas and sends signals to the substantia nigra pars reticulata.
• Nucleus Accumbens: Involved in reward processing, motivation, and emotional regulation.
• It is the main area where information enters the basal ganglia.
• Degeneration of striatal neurons leads to movement disorders like Parkinson’s and Huntington’s.
• Two inputs to the striatum: cortical projections (glutamate, excitatory) & substantia nigra projections (dopamine, excitatory or inhibitory) with D1 receptors being excitatory and D2 receptors being inhibitory.
• 90% of the striatum comprises GABAergic or inhibitory projection neurons.

Basal Ganglia - Globus Pallidus

• Positioned medial to the putamen, forming the lenticular nucleus.
• Globus pallidus receives input from the striatum and sends inhibitory outputs to the thalamus.
• Globus pallidus external (GPe) relays information to the globus pallidus internal (GPi).
• Globus pallidus internal (GPi) is one of two output nuclei of the basal ganglia, exerting control over the thalamus.
• GPe + GPi + Putamen = Lenticular (Lentiform) Nucleus.
• Pallidal outputs are inhibitory to the subthalamic nucleus in the thalamus.

Basal Ganglia - Outputs

• The primary output region is the internal segment of the globus pallidus.
• Sends inhibitory GABAergic projections to the thalamus.
• The thalamus then projects back to the cerebral cortex, primarily to motor areas.

Basal Ganglia - Substantia Nigra

• Two parts:
  • Pars Reticulata (SNr): Sends inhibitory signals to the GPi.
  • Pars Compacta (SNc): Produces dopamine.
• Name means black substance due to high levels of melanin.
• Essential for controlling body movements by producing dopamine.
• Globus pallidus tapers into the midbrain as the reticular part of the substantia nigra.
• Pars reticulata inhibits brain cell activity with GABA, while the pars compacta produces dopamine.
• Dopamine is released during pleasurable activities & contributes to focus, retention, well being, and happiness.
• Substantia nigra is tonically active.
• Degeneration of neurons in the substantia nigra is a primary feature of Parkinson’s disease.
• Results in lower levels of dopamine = Balance and coordination problems, muscle weakness, and spasms, shakiness and tremors, lack of focus, trouble thinking, and difficulty with eye movements.

Basal Ganglia – Subthalamic Nucleus

• Composes the majority of the subthalamus.
• Plays a role in motor integration and body movement accuracy.
• Important for the inhibition of unwanted movements.
• Sends excitatory signals to the internal globus pallidus, which inhibits the thalamus.
• Subthalamic nuclei are the only glutamatergic neurons in the basal ganglia.
• Part of the indirect pathway that controls motor function.
• Clinical: Lesions can cause decreased stimulation of the globus pallidus internus, with consequent disinhibition of the thalamus and hyperkinetic movements.
• Damage can lead to hemiballismus (uncontrolled violent movement on one side of the body).

Basal Ganglia – Connections

• Cerebral cortex (motor control, cognition, sensory processing): Inputs directed to the striatum (caudate nucleus + putamen).
• Thalamus: Transmits processed signals from the BG and projects them back out to the cortex; “Feedback Loop”.
• Cerebellum: Ensures fluid and accurate motor execution.
• Limbic System: Integrates emotional and motivational states with motor actions.
• Pre-Frontal Cortex: Guides and supports goal-directed behaviors and the formation of habits.

Basal Ganglia – Pathologies

• Parkinson's Disease: Progressive neurodegenerative disease from loss of dopamine causing tremors, stiffness, bradykinesia, and balance issues.
• Hemiballismus: Damage to the Substantia Nigra resulting in sudden, violent, large-amplitude movements.
• Huntington’s Disease: Hereditary neurodegenerative disorder (mutation of HTT gene) causing “chorea,” behavioral changes, and dementia.

Basal Ganglia – Circuits

Direct vs. Indirect Pathways

• Direct Pathway ("Go"): Yields increased movement initiation.
• Indirect Pathway ("No-go"): Yields inhibited movement.

Direct Pathway

• Cortex sends excitatory glutamate projections to the striatum (D1 receptors).
• Striatum sends inhibitory GABA projections to the internal segment of the globus pallidus.
• Internal segment of the globus pallidus sends inhibitory GABA projections to the thalamus.
• Thalamus sends excitatory glutamate projections to the cortex.
• Direct pathway activation promotes movement by reducing thalamus inhibition.

Indirect Pathway

• Cortex sends excitatory glutamate projections to the striatum, which are part of the indirect pathway.
• Striatum sends inhibitory GABA projections to the external segment of the globus pallidus.
• External segment of the globus pallidus sends inhibitory GABA projections to the subthalamic nucleus.
• Subthalamic nucleus sends excitatory glutamate projections to the internal segment of the globus pallidus.
• Internal segment of the globus pallidus sends inhibitory GABA projections to the thalamus.
• Indirect pathway increases inhibition on the thalamus, reducing its ability to activate the cortex and suppressing movement.

Summary of Internal Processing

• Cortical activation of the direct pathway leads to increased thalamic output.
• Cortical activation of the indirect pathway leads to decreased thalamic output.
• Substantia nigra activation (via D1) of the direct pathway leads to increased thalamic output.
• Substantia nigra inhibition (via D2) of the indirect pathway leads to increased thalamic output.

Basal Ganglia Loops

• Motor loop = Concerned with voluntary and learned movements
• Cognitive loop = Concerned with planning a motor intentions.
• Limbic loop = Concerned with emotional aspects of movement
• Oculomotor loop = Plays a role in voluntary eye movements.