The Reward Circuit - a brief overview

My current research project makes use of positive feedback as a form of reward or incentive in learning. This is actually exciting as it combines motor learning processes and positive reinforcement. Reinforcement and reward-based learning implicate the limbic network, in which the basal ganglia, BG, is one of the most important members. Specifically, it is the ventral portion of the striatum called the nucleus accumbens (NAcc) and underlies a series of behavior e.g., motivation, and emotion. Initially thought as purely motoric, BG evolved to engage more diverse behavior such as executive, and then the limbic functions. The inclusion of the limbic region as a part of the BG has also been proven anatomically (Nauta, et al., 1978; Mogenson et al., 1980; Haimer et al., 1986). More importantly, the BG limbic circuit does not work in isolation. This summary will be based on an excellent review by Haber and Knutson (2010) and a few other relevant good stuffs will be provided as references at the end.

Neuroanatomy of Reward
Prefrontal Reward Regions
The involvement of prefrontal cortex in reward comes naturally. Scientists have been interested in studying the role of the frontal lobe in cognition in which reward processing is one of the main features. The main reward-based prefrontal regions traditionally include the anterior cingulate cortex (ACC) that includes BA 24, 25, and 32 and the orbitofrontal cortex (OFC) that includes BA 11, 12, 13, and 14. Unlike sensorimotor cortex, the prefrontal cortex is diverse in terms of cytoarhitectonic features and functions. The recent paper in PNAS (Neubert FX, et al, 2015) scrupulously describes similarities and differences between primate and human prefrontal cortex associated with reward. In general, the human prefrontal cortex is sub-divided into a few areas:
  (a) Sensory region: the orbital part of the brain linked to the olfactory bulb and the insula.
  (b) Ventromedial prefrontal cortex (vmPFC) that includes BA 10, 11, and 32.
  (c) Rostral OFC that covers BA 11, 12, and 13.
  (d) Dorsal ACC or dACC that is BA 24.

Reinforcement-based motor learning presumably implicates basal ganglia (Schultz et al., 1997; Graybiel, 2005). In fact, reward-based action may involve more complex neuronal processes beyond the traditional basal ganglia and sensorimotor loops. For example, it is possible that reward-based decision-making is also involved (Rushworth et al., 2004), such that during learning rewards may influence the production of subsequent movements. Prior studies show that regions in the prefrontal cortex are involved in this type of activity (Shima and Tanji, 1998). Using fMRI in gambling tasks (Daw et al., 2006), it has been shown that the intraparietal sulcus and frontopolar cortex are preferentially active during exploration. In contrast, regions of the striatum and ventromedial prefrontal cortex are involved in exploitative decision making to accumulate more rewards. The vmPFC is a region in which activity is associated with stimulus-reward value, selecting actions that are more rewarding (O'Doherty et al., 2003; Rushworth et al., 2004; Daw et al., 2006) and encoding the value of performed decisions (Knutson et al., 2001; Smith et al., 2010).

The Ventral Striatum
In 1954, Olds and Milner discovered how a tiny structure called the NAcc that lies ventral to the sensorimotor striatum is linked to reward behavior in rats. In 1978, Heimer described the link between NAcc and olfactory tubercle in rats. Ventral striatum was later regarded as the reward center and thought to be the interface between the limbic and motor systems (Mogenson et al., 1980). In recent years, the traditional boundaries of ventral striatum have expanded beyond NAcc which includes the ventral portion of the striatum and the ventral caudate. Thus, the name ventral striatum (VS) is legit to contrast this with the more dorsal, sensorimotor-related striatum. The NAcc structure has an outer shell and a core, each contains different neuronal cell types and functions.

(1) Afferent projections
Like the dorsal sensorimotor striatum, VS receives massive topographic glutamatergic inputs from the cerebral cortex, from the thalamus, and the brain stem. The word topographic deserves an emphasis, refer to Fig-2. From the prefrontal reward regions, vmPFC sends projections mainly to the NAcc. From NAcc, we go more dorsally and laterally to regions that cover ventral caudate nucleus and ventral putamen. Principally, these two areas receive projections from the OFC. The dACC also projects to a more central and lateral portion of caudate and putamen. Lastly, the DPFC (dorsal prefrontal cortex) terminates more diffusely along the rostro-caudal striatum, particularly the head of the caudate. A critical difference with the dorsal striatum, VS also receives projections from the amygdala and hippocampus. The afferent axons are concentrated within the NAcc. Amygdala is known to play a role in processing reward, e.g. an emotional aspect of reward, associating stimuls and reward or punishment. Thalamus is the final link connecting VS with the rest of the brain regions. In the thalamus, reward processing is managed by one of the largest nuclei there called the medial-dorsal nucleus (MD) that carries bidirectional wiring between the frontal lobe and VS, amygdala, and hippocampus.

(2) Efferent projections
Like the dorsal sensorimotor striatum, VS sends efferent axons to two main targets. First, the more specific efferent outputs to the ventral pallidum, not GPe or GPi. Second, more broad midbrain regions such as the ventral tegmental area (VTA) and middle substantia nigra (SNpc) which are rich of the dopaminergic neurons. The pathway between midbrain and VS is known as the mesolimbic pathway and is known to mediate reward processing. Other efferent projections are to the pedunculopontine nucleus (PPT) and nucleus basalis (NB, the principal source of cholinergic fibers to the cortex and amygdala). In particular, PPT carries broad functions such as arousal, attention, motivation, and voluntary limb movements.

Midbrain dopamine neurons
The involvement of dopamine in reward is perhaps first shown elegantly by the work of W. Schultz since 1970s. The VTA and SNpc, the substantia nigra pars compacta, are two important components and their neurons can be identified using a certain phenotypic marker, e.g. calbindin for dorsal SNpc and VTA (the ventral SNpc, however, is calbindin-negative).

(1) Afferent projections
The principal inputs to VTA/SNpc come from the striatum through both the GPe and VP. Other inputs come from other parts of the brain stem, mainly PPT. Anatomically, the largest source of projection comes from the ventral striatum.

(2) Efferent projections
Midbrain dopamine neurons send massive projections out back to the striatum through the mesolimbic pathway mentioned above. It has been found that there is a medio-lateral and an inverse dorso-ventral topography arrangement. Thus, the ventral portion of SNpc projects to the dorsal striatum, the dorsal portion projects to the ventral striatum. It has also been observed that there is differential efferent projections back to the striatum. In other words, VS receives the least number of projections while the sensorimotor striatum receives the most. This striato-nigro-striatal network is consistent with the idea that the limbic system is able to influence sensorimotor behavior through the interface situated in the striatum. Apart from the striatum, dopamine neurons from the midbrain send rather diffuse projections to the frontal lobe through the mesocortical pathway, so it is wrong to say that BG is the only target of dopamine in the brain.


Further Readings
[1]  SN Haber, Knutson B. (2010). "The reward circuit: linking primate anatomy and human imaging". Neuropsychopharmacology.
[2]  FX Neubert, et al. (2015). "Connectivity reveals relationship of brain areas for reward-guided learning and decision making in human and monkey frontal cortex". Proc. Nat Acad. Science.

More on Basal Ganglia & Cerebellum

The themes concerning basal ganglia and cerebellum have been summarized in my previous blog post. Both structures have been traditionally known to play dominant roles in voluntary movements. However, as time goes by, such roles have developed into a wider perspective related to non-motor functions such as general learning, executive functions, and emotion.

Functional topography of Basal Ganglia
There is a convergence of cortical information in the striatum from the cortex. This means that axons of cortical neurons terminate on a far smaller number of striatal neurons, Similarly, the number of neurons in the pallidum and substantia nigra is smaller than that in the striatum, allowing further convergence along the direct and indirect pathways. There also seems to be a somatotopic organization with the cortico-striatal-thalamic pathways. Evidence mainly comes from animal studies using tracers systematically injected into the monkey brain. This includes projections from GPi to the M1, SMA, and premotor cortex (Hoover & Strick, 1993; Akkal, Dum, & Strick, 2007), to Area 7b in the parietal lobe (Clower, Dum, and Strick, 2007).

Important evidence showing how BG is involved in cognitive processes has been shown anatomically through the work of Middleton and Strick (2002). The authors injected a few different prefrontal areas such as Area 9m /9l, Area 46v/46d, and Area 12l ['m' and 'l', 'v' and 'd', 'l' stands for medial/lateral, ventral/dorsal, and lateral respectively]. They found that labels associated with these areas comprised almost 1/3 of the GPi, indicating the importance of BG for executive tasks.

Non-motor Aspects of Basal Ganglia
Although in the early days, scientists thought that BG is important only for sensorimotor functions, there has been considerable acceptance of the four parallel divisions or systems in BG. They include circuits responsible for the skeletal/sensorimotor system, oculomotor system, executive functions, and limbic functions (Alexander et al, 1990). The oculomotor system engages the frontal eye field (FEF) and the supplementary eye field (SEF) anterior to the dorsal premotor cortex (PMd). From these two areas, projections go into the caudate area of the striatum and in turn controlling the SNpr/GPi via the direct pathway before going out to the superior colliculus (brain stem). The oculomotor system is very important for saccadic eye movements and memory-guided saccades.  Refer to the figure below.

Fig-1:  Four different basal ganglia functional divisions (adapted from Kandel, 5e)

The prefrontal cortex subserves higher-order behavior such as cognitive control, reasoning, problem-solving, general attention, working memory, which are collectively known as the executive functions. Two areas, the dorsolateral prefrontal cortex (DLPFC) and lateral orbitofrontal cortex (LOFC), project to the dorsal caudate of the striatum. DLPFC is important for organizing behavioral responses to complex problems and using verbal skills in problem-solving. LOFC, on the other hand, controls empathy and socially-appropriate behavior. The limbic circuit [Nauta, 1986 for review] begins with projections from the anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (MPFC) to the ventral striatum, which also receives input from the memory structures: hippocampus, amygdala, and entorhinal cortices. The ACC/MPFC complex is important for motivating behavior and reinforcement learning.

Patients with cerebellar damage
When a person performs skilled and goal-directed movements, the cerebellum maintains accurate and timely limb movements. One influential idea says that the cerebellum is crucial for error-based motor adaptation. Prior evidence that point to this idea comes from studies involving visuomotor and force-field adaptation (e.g. the works from Amy Bastian or Reza Shadmehr). In 1970s, Marr and Albus independently suggested that the cerebellum may be involved in motor learning. This is associated with the concept of plasticity between the Purkinje cells and parallel fibers inside the cerebellar cortex. Ito later proposed the role of complex spikes from the climbing fibers as the learning signal. Experiments using motor adaptation have shown that people with cerebellar damage impacting climbing fibers aren't able to adapt to both force-field and visuomotor perturbation.

The output gates of the cerebellum are located in the deep cerebellar nuclei in the white matter. These nuclei send projections back to the cortex via the thalamus, and they are strongly excitatory necessary to maintain muscle tone. This, however, isn't related to strength but more on the timing. Lesions of the interposed nucleus reduce the accuracy of reaching movements because of errors in timing, in direction and extent, in straightness due to poor joint coordination. The hand oscillates irregularly around the target. Neurological examinations show that damage to cerebrocerebellar path delays movement timing (Holmes G., 1939). A complex movement can be decomposed into a sequence of movement components. In healthy people, this decomposition is not obvious as the movements are performed smoothly and timely.

Experiments with primates help to elucidate the role in the motor disruption. When a monkey is trying to keep its arm in a fixed position, the application of a force to extend the elbow triggers a stretch reflex in the biceps. This will pull the arm rapidly and precisely to its initial location. The contraction of the extensor triceps plays a dominant role in keeping this precision, preventing the elbow from overshooting after the biceps contract. This appears as an anticipatory mechanism, i.e. feed-forward control. When the two deep cerebellar nuclei, dentate and interposed nuclei are deactivated, the arm oscillates instead of firmly going back to the original position. There seems to be an excessive, yet inaccurate, feedback correction (Vilis, Hore, Flament, 1984 & 1986).

Different Cerebellar Lobules
Like the cerebral cortex, the cerebellar cortex can be divided into four functional divisions: the vermis, intermediate zone or paravermis, lateral hemispheres, and flocculonodular lobe. Animal studies, in particular, in rats and cats have been used as models for anatomical studies. Perhaps, the most popular and classic human cerebellar anatomy comes from the works by Larsell & Jansen (1970). Refer to the Fig-2 below. The lateral hemisphere is especially important because of its massive connections with the cerebral cortex. Both vermis and the lateral hemisphere ('H') are further divided into nine subdivisions or lobules, each assigned a Roman number I to IX.

The earlier attempts to localize cerebellar functional organization were done as a result of lesion studies in both higher-order mammals and humans. Like the sensorimotor cortex, the existence localization and cerebellar somatotopic map do not represent the bodily extent, but rather, the functional demand. A series of the different somatotopic maps were released by Bolk (1904), Adrian (1943), and Snider & Stowell (1944). The progress continued with the help of tracers and, more recently, neuroimaging. Using fMRI, Grodd et al. (2001) did an elegant study producing sensorimotor topography of the cerebellum. The study was based on 46 human subjects performing a series of motor tasks such as opening/closing of right/left fist, extending right/left arm and leg, and moving the lips. I also recommend another article by Manni & Petrosini (2004) in Nature Rev. Neurosci. for a more elaborated summary with historical contexts. The following diagrams are taken from their paper.

Fig-2: Gross anatomy of the cerebellum (right, after Larsell & Jansen) and functional map (left, after Grodd et al.). Both vermis and the lateral hemisphere ('H') are subdivided into lobules. Of utmost interest is the left somatotopic map. The arms are represented by Lobule V-VI. In particular, fine motor control of the hand and fingers are by Lobule VI and VIII of the lateral hemisphere. Note that the connections to bodily parts are ipsilateral.



The involvement of non-motor functions are shown by the neuroimaging work by Stoodley et al (2012), They found right-handed finger-tapping activated right cerebellar lobules IV–V and VIII. Verb generation engaged right cerebellar lobules VI and Crus I and a second cluster in lobules VIIB–VIIIA. Furthermore, mental rotation activated medial left cerebellar lobule VII (Crus II). Lastly, 2-back working memory task activated bilateral regions of lobules VI–VII.

Important Anatomical Connections
Studies elucidating specific connections between the cortex and cerebellum have been done using anatomical tracers in animals. For example, retrograde transneuronal transport with herpes simplex virus, HSV1, was injected into the cerebral cortex of Cebus monkeys to label neurons in the dentate nucleus (Dum & Strick, 2003, Akkal, Dum, & Strick, 2007). With sufficient survival time, it was enough to reveal a set of first-order neurons in the thalamus, and second-order neurons in the dentate nucleus. Dentate nucleus was targeted by researchers at the time as the shape is the largest and easily recognized. The study showed different dentate output channels to the motor areas (M1 and SMA) and non-motor regions in pre-SMA, Area 7b, Area 46, and Area 9L.

Another important study adopting both retrograde and anterograde tracers is by Kelly & Strick (2003) that reveals the existence of cortico-cerebellar loop in both motor and non-motor domains. In the motor loop, neurons in M1 project to cerebellar lobules V, VI, and HVIIB and HVIII, and project back to the same regions of cortex via dorsal parts of the dentate nucleus and the motor thalamus. In the prefrontal loop, however, Area 46 projects to lobule HVIIA/B (mainly to Crus II) via the pontine nuclei, and returns back to the same areas of the prefrontal cortex via ventral parts of the cerebellar dentate nucleus and prefrontal thalamus. This segregated domain also confirms the neuroimaging works mentioned above, separating motor and non-motor areas in the cerebellum. Lobules that are connected to prefrontal regions are considered non-motoric. Refer to Fig-3.

Fig-3:  Anatomical projections from the cerebral cortex and cerebellum forms loop (from Kelly & Strick, 2003)

Basal ganglia and cerebellum receive inputs from cortical motor areas and send projections back to the same areas. These multisynaptic links suggest the extent of influence of both structures to movement production. Most anatomical connectivity has been revealed by tracing studies done by Strick and his group. For example: injections of retrograde tracing to a specific area in M1 or SMA (e.g. arm) with right survival time have revealed how neurons in the dentate nucleus and internal segment of the globus pallidus are labeled. In fact, there seems to be clear functional segregation (e.g. arm, face, digits) in both dentate nucleus and GPi. This suggests that neurons in both the cerebellum and basal ganglia do project to the motor cortex. However, there is no direct connectivity between basal ganglia and cerebellum.

From Neuroanatomy to Cognition

White Matter Fibres
The white matter was briefly mentioned in an earlier post, so this is sort of a continuation of the brain's gross anatomy. The white matter is located underneath the cortical gray matter and composed of fatty myelinated axons. It is an integral part of the central nervous system that transmits messages very rapidly. It basically has 3 types of fiber bundles: the projection fibers, commissural fibers, and association fibers.

1. Projection fibers are bi-directional, afferent, and efferent bundles. They appear as radiating bundles in the white matter that exit the cerebral cortex and converge towards the brainstem. One bundle carries visual information through the optic radiation. Near the subcortical nuclei, these axons form a compact band known as the internal capsule with anterior and posterior limbs. Afferent (sensory) fibers: mainly the thalamocortical bundles going to the various region of the cerebral cortex. The efferent fibers of the internal capsule arise from the cerebral cortex. They form various tracts, e.g. corticothalamic, corticobulbar, corticospinal, and corticopontine bundles. 
2. The axons part of the corpus callosum forms the commissural fibers. At different callosal segment, they have different connections: the rostrum (orbitofrontal), genu (frontal lobe), body (sensorimotor and posterior parietal), and splenium (posterior temporal and occipital). Other commissural fibers are the anterior commissure, connecting the olfactory system bilaterally.
3. The association fibers form the bi-directional cortico-cortical bridges connecting areas within the same hemisphere. They can be classified as short and long fasciculus:
        - Superior longitudinal fasciculus connects frontal and parietal lobes.
        - Occipito-frontal fasciculus connects frontal and occipital lobes.
        - Arcuate fasciculus connects the frontal with posterior temporal lobes.
        - Uncinate fasciculus connects orbitofrontal with anterior temporal lobes.
        - Inferior longitudinal fasciculus connects temporal and occipital lobes.
        - Extreme capsule fasciculus connects lateral temporal and lateral frontal lobes.

Of interest is the coronal section of the cerebral hemisphere from the insula moving inwards to the thalamus. The external capsule connects the motor cortex to the putamen and is unidirectional. The internal capsule connects specific thalamic nuclei to the specific cortical area and hence it is bidirectional.

The most common way to study the white matter is through MRI which can be observed well on T1-weighted, T2-weighted, and FLAIR sequences. More recently, scientists become more interested in modeling brain development over puberty and brain decline associated with aging. Fun facts: Gray matter volume increases in early childhood but declines after puberty. However, white matter volume progressively increases over time, supporting the concept of neural plasticity.

Cerebral organization
The cerebral cortex is organized into six layers that arise from the time of its development. This is the characteristic of the neocortex. Only the piriform cortex and the hippocampal formation, the oldest cortical structures phylogenetically or paleocortex or allocortex, do not exhibit this six-layer arrangement. The projection fibers are more deep-rooted, while the association and commissural fibers are more superficial. Three principal types of cells found in the cortex include the pyramidal, stellate, and fusiform neurons. Their fibers are arranged either tangentially or radially across layers.

Pyramidal cells, with a shape of a triangle with the top end going up to the surface (apical) and the horizontally running dendrites (basal), constitute the most in various cortical layers. The axons are either going down to the white matter (as projection fibers) or to other cortical areas (as association fibers). The biggest pyramidal cell, the Betz cell, is found only in Layer V of the precentral gyrus or motor cortex. Unlike pyramidal cells, granule or stellate cells are small, polygonal or triangular in shape. They are found in all layers, but especially numerous in Layer IV. Fusiform neurons are spindle-like cells found mostly in the deepest cortical layer, their long axis going vertically upward. Apart from these three types of cells, we encounter others, e.g. horizontal cells found mostly in the superficial layers. The works of Cajal and Golgi are crucial in deepening our understanding on these cells.

Fig-1: Six different cortical layers of the cerebral cortex, layer-I being the most superficial.

In brief, six-layered architecture can be described as follow:
a). Layer I (molecular layer), has few cell bodies, mostly axons, Layer II (external granular layer).
b). Layer III (external pyramidal layer), cells forming mainly association or commissural fibers.
c). Layer IV (internal granular layer), mainly the incoming afferent fibers from the thalamus.
d). Layer V (internal pyramidal layer), mainly efferent projection fibers.
e). Layer VI (multiform, fusiform layer).

What is the relationship between this architecture with the earlier functional lobes? Layer III plays a major role in cortico-cortical connections. Layer IV is predominant in sensory areas in the parietal and temporal lobes, e.g. the postcentral gyrus. These regions are granular. Layer V, on the other hand, is predominant in motor areas, e.g. precentral gyrus.

Fig-2: The distribution of different cortical composition: (1) Agranular; (2) Granular - frontal (dysgranular); (3) Granular - parietal; (4) Granular - occipital; and (5) Koniocortex. Only cortical motor areas are agranular.

Principal neurotransmitters

A variety of neurotransmitters is associated with neurons of the cerebral cortex. Among those, we have glutamate, aspartate, and γ-aminobutyric acid (GABA). Pyramidal cells are the main efferent neurons that are predominantly glutaminergic and are excitatory. Most interneurons within the cortex, however, are GABAergic and are inhibitory. They are bridging the afferent and efferent fibers together. Therefore the outputs of the cortex are modulated by a variety of cortical afferents via interneurons. 

A variety of neuropeptides or monoamines are also found in the cerebral cortex; they influence not only populations of neurons but also local metabolic activity and vascular smooth muscle. The most important monoamines in the cortex are (1) norepinephrine, which originates from the locus ceruleus of the pons and distributes sparsely to all cortical layers; (2) dopamine, which arises from the substantia nigra–pars compacta and the adjacent ventral tegmental area and is found in moderate amounts in layers I and VI and sparsely in layers II to V; and (3) serotonin, which arises from the raphe nuclei and distributes heavily to all cortical layers.

Cognition and the Brain
The study of human cognition and the brain is the heart of a classic science popularly known as neuropsychology. The interests existed since the time of Descartes, Gall, Broca, and so on, who studied the link between a neurological condition (e.g. lesions) and certain behavioral or psychological processes. A classic theory, phrenology, says that the brain is divided into discrete and unique areas responsible for a particular function only. The mastery of certain skills can be deduced by the bigger skeletal landmark of the head. An opposing view at that time held that there is no localization of brain functions and that the functions (what they called "Mind") are distributed across different parts of the brain. With more discoveries, modern neuroscience later thought that the brain is divided into many functional specialization. For example, one may use fMRI to elucidate brain areas associated with some behavioural tasks. One fundamental characteristic of the central nervous system is parallelism, that is, a large number of functions are simultaneously processed along two or more pathways. As a result, the damage of one pathway can allow other pathway to function, and that one brain function can be performed not only strictly by one area. 

Modern neuropsychology enjoys a multidisciplinary collaboration among cognitive scientists, physiologists, neuroscientists, and clinical psychologists. Originally, the field drew strong attention when Paul Broca came into contact with a patient undergoing a progressive speech disorder in 1861, who could only produce "tan". After the patient died, Broca found out that his inferior frontal gyrus (IFG) was damaged. Named after Broca, the type of such behavioral deficit linked to the damage of IFG is then called Broca's aphasia. Note: IFG is rostral to the mouth/orofacial musculature of the cortical motor area.

Fig-3: The difference between Broca's and Wernicke's aphasia together with affected areas on the left hemisphere.

Broca's finding was further developed with the findings of Carl Wernicke. He found that in a certain type of language disorder, the patients were able to produce speech but unable to comprehend the conversation. Called Wernicke's aphasia, the damage is found to be around the posterior part of the superior temporal gyrus (STG). This aphasia is not equal to deafness, for the person with Wernicke's aphasia is able to detect sound but unable to make sense of it. He further hypothesized that there is a link between IFG and STG and this is crucial in language. To be able to converse well, one has to first listen and understand the sentences one hears. Note: STG is near to the primary and secondary auditory cortex.

In the 1870s, John Hughlings Jackson proposed that the cerebral cortex is organized hierarchically and that some cortical areas are for higher-order functions (or cognitive) that are neither fully sensory nor motor. These brain areas are called association areas because they serve to associate sensory inputs to motor response and conduct mental processes related to sensorimotor behavior. The mental processes that Jackson attributed to these areas include interpretation of sensory information, the association of perceptions with previous experience, focusing of attention, and exploration of the environment. Jackson's finding is supported by clinical works. The major helps come from surgical rooms of patients with damage or lesion on the specific are, or people with underlying conditions. Other methods include experimental studies with monkeys and rats and the use of non-invasive brain imaging technology.

Before ending, I wish to mention major associative areas in the human brain important in cognition:

1. The posterior association area: the margin of the parietal, temporal, and occipital lobes. It integrates information from several sensory modalities such as vision, space, and body senses. It is also involved in language. Separate studies by Holmes and Luria on wounded soldiers found that bilateral injuries to the posterolateral parietal lobe yield to normal visual acuity but the soldiers were unable to scan visually or reach for an object of interest. They could not process together with the visual information when asked to describe in words what that they saw. This shows that the region is critical for integrating different sensory modalities and for using that integrated information to direct behavior. 
2. The anterior association area: the prefrontal region, rostral to postcentral gyrus. It is involved in the planning of action, shaping behavior, and judgment; a more popular term is the "Executive function". The most popular case showing how the injured prefrontal region leads to behavioral problems is perhaps of Phineas Gage. A series of clinical tests, e.g. the Tower of London test and the Wisconsin Card Sorting Test (WCST), can be used to diagnose people with neuropsychological disorders who have lost their executive functions, such as schizophrenia. WCST is primarily considered a test of executive functions, particularly abstract reasoning and cognitive flexibility in response to external changes.
3. The limbic association area: along the lower medial end of the cerebral hemisphere. It is for emotion, learning, and memory. Its involvement in learning and memory comes from the well-known study on patient H.M. by B. Milner in 1960s after both medial temporal lobes had been removed. She first demonstrated the remarkably selective role of this part of the brain in converting short-term into long-term memory. Studies in monkeys have helped establish that association areas in the medial temporal lobe, including the hippocampal formation, receive information from virtually every other association area. In other words, the hippocampal formation is able to sample the whole stream of ongoing cognitive activity and thereby relate different aspects of a single event so that they can be recalled as a coherent experience.

More recently, cognitive neuroscience is recognized as another separate field, combining neuroscience, neurophysiology, and psychology. Scientists now agree that the three areas (the triad) of executive function are working memory, flexible thinking, and inhibitory control.

Gross Anatomy of The Brain

This is a huge topic. It should have been published the first in my blog, but it's still not too late to do it now I guess. The gross anatomy of the brain is fundamental knowledge every neuroscientist has to know.

Fig-1: The main divisions of the central nervous system (top-left), together with major anatomical axes; adapted from [1].

The Forebrain: Telencephalon
We usually refer to this part of the brain as the cerebral hemisphere. It consists of the cerebral cortex and the subcortical region beneath it. The cerebral cortex serves as the main computational unit and contains mainly cell bodies and glass. That's why its appearance is grayish tan, also known as the gray matter. On the other hand, the subcortical region consists mainly of myelinated axons and therefore it is called white matter. The forebrain is encapsulated inside a layer of cerebrospinal fluid or CSF a colorless fluid important for mechanical and immunological protection. The ventricles also contain CSF.

1. The cerebral cortex.
This is the outermost layer of the cerebral hemisphere. In humans, it is greatly convoluted and consists of: sulci (sulcus - singular) or small grooves, fissures (large grooves), and gyri (gyrus - singular) which are bulges between adjacent sulci or fissures. What's the reason behind it? Well, by "hiding" most of the cortical areas in the grooves, we have a much bigger brain region, suggesting a more computational advantage. The thickness is ~ 3 mm with a total surface area of 0.24 m². K. Brodmann was the first person who did an excellent job identifying various cortical areas based on cytoarchitectonic features, that is, differences in cortical layer architectures.

Traditionally, the cerebral cortex is divided into 4 regions, i.e. frontal, parietal, temporal, and occipital. The frontal lobe is known for motor and executive functions. Three regions of the cerebral cortex are sensory, meaning, they receive afferent inputs from the peripherals, sensory organs:

• The primary visual cortex (V1, BA-17), on the occipital lobe.
• The primary somatosensory cortex (S1, BA-3, BA-1, BA-2), on the parietal lobe.
• The primary auditory cortex (A1, BA-41), on the temporal lobe.
• The other two are hidden, i.e. the primary olfactory cortex, near the piriform cortex, and primary gustatory cortex, near the insular cortex. 

With the exception of olfaction and gustation, sensory information is sent from the contralateral side of the body. Regions adjacent to the primary sensory area are called the association areas which are involved in more higher-order cognition and perhaps memory. Their lesions are insightful to understand their functions. Patients with damage to S1 are unable to perceive tactile sensation and recognize the object in general. Clearly, S1 sends projections to the adjacent association area. Damage to the somatosensory association cortex allows the person to sense the presence of the stimuli, but he or she is unable to recognize, call or name, or perceive the shape or contour or the objects.

The regions further away from these primary areas, e.g. around the border of temporal, occipital, and parietal lobes, are called multimodal sensory areas where multisensory integration occurs. The region of the prefrontal cortex is involved not with movement or sensory perception, but with formulating plans and strategies. To plan and make a decision, we have to depend on the current sensory inputs, past experience or memory, and action selection (sometimes called executive functions).

2. The basal ganglia and subcortical structures.
Regions immediately below the cerebral cortex form the white matter and the subcortical structures. Some of the most important structures are the amygdala, fornix, parts of the hypothalamus. Amygdala, together with parts of the cingulate gyrus and parahippocampal gyrus of the cerebral cortex, are parts of the limbic system. These structures play a role in learning and emotional expression. Immediately below the cingulate gyrus is the corpus callosum. Immediately above it is the folding or sulcus, originated from the medial wall and goes down to the rostral end beneath the prefrontal cortex. This folding, called the cingulate sulcus, separates the frontal lobe and the cingulate gyrus. Amygdala is important for emotion and recognizing the emotional reactions of others.

More discussion on basal ganglia is in a separate blog post. Large and intricate bundles of fibers called the fasciculi form what is known as the white matter. Some of these fibers pass through the nuclei of the basal ganglia forming the internal, external, and extreme capsules. This part will not be presented here.

The brain has two hemispheres separated by the longitudinal fissure. Are the two hemispheres talking to each other? Yes, and the left parietal region knows what the right one is doing; and this is the job of the corpus callosum, containing bundles of commissural fibers, i.e. neurons that connect the two cerebral hemispheres. Another type of fibers which allows different cortical regions of the same hemisphere talk to each other is called association fibers.

The Interbrain: Diencephalon
The structure of diencephalon is quite small. It is located between the telencephalon and mesencephalon around the third ventricle. There are two main components, i.e. the thalamus and hypothalamus, both contain two lobes spanning the right and left hemisphere. In the medical field, the hypothalamus has been known as a thermostat to control body temperature. The thalamus and hypothalamus are further subdivided into several regions or nuclei, each of which contains a collection of neuronal cell bodies with a distinct functional role.

Thalamus is composed mainly of projection fibers, i.e. axons of the neurons from one part of the brain that form a synapse with the neurons of another region. The hypothalamus is important in controlling the autonomous nervous system, endocrine or hormonal system, and survival-related behaviors. Pituitary gland serves as the master gland because it controls the secretion of other endocrine glands (the details are not presented here). Anterior to the pituitary gland is the optic chiasm where optic nerves from both eyes cross.

The Midbrain: Mesencephalon
Midbrain is the middle portion of the brain surrounding the cerebral aquaduct. There are two major components: the tectum and tegmentum. Tectum is the dorsal part of the midbrain containing 2 principal structures: a pair of superior colliculi (part of the visual system) and a pair of inferior colliculi (part of the auditory system). Tegmentum is situated beneath the tectum and includes several important midbrain nuclei such as the rostral end of the reticular formation, periaqueductal gray matter, red nucleus, substantia nigra, and the ventral tegmental area. The last two structures are well-known as the source of dopamine.

The Hindbrain: Metencephalon and Myelencephalon
The hindbrain consists of the cerebellum, pons, and medulla. The part on the cerebellum, in itself the 'small brain', is being presented elsewhere in this blog. The two remaining regions, pons, and medulla (or medulla oblongata), are part of the brainstem and located anterior to the cerebellum.

Pons contains part of the reticular formation and pontine nuclei. It is involved in the facial somatosenses and automatic repetitive movements such as breathing and swallowing. The medulla is the most caudal region of the brainstem, adjacent to the rostral end of the spinal cord. As a very important structure in the autonomic nervous system (ANS), the medulla controls respiration, cardiac rate, and some other reflex centers such as swallowing, coughing, and sneezing.

Fig-2: Anatomy of the brainstem with the right hemisphere of the cerebellum. Adapted from [2].

What is beyond the cortex? Well, the central nervous system (CNS) consists of both the cerebral cortex and the spinal cord. The brainstem connects the cortex with the spinal cord. A more detailed part will be for another blog entry but the gist is this:

1. The white/gray matter location is swapped as you enter the spinal column. As we know, white matter contains myelinated axons, while gray matter contains cell bodies. The center gray matter core of the spinal cord is made up of cell bodies of spinal interneurons that connect motor-motor, motor-sensory (as in reflex arc), and propriospinal neurons. Indeed, the anatomical connections are rather intricate!
2. The central core has an inverted H-shaped. It is divided into ventral (motoric) and dorsal (somatic). Mechanoreceptors send information to the sensory neurons whose cell bodies are in the dorsal root ganglion. They enter the spinal cord through the dorsal side up. On the other hand, pyramidal cells from the motor cortex enter the spinal cord through the ventral horn where they synapse with the alpha motor neurons that target a specific muscle.
3. The spinal cord is important for low-level, stereotyped reflex behavior, as well as locomotion.

Appendix: The cerebral cortex
I want to add some more information regarding the cerebral cortex. In particular, with regards to the Brodmann Areas.

Fig-3: Parts of parietal, temporal, and occipital lobes: a The area V1, V2 and V3 of the occipital lobe (BA 17, 18, and 19). b The area postcentral gyrus, superior parietal lobule (BA 5, 7), and inferior parietal lobule (consisting angular gyrus or BA 39; and supramarginal gyrus or BA 40). c The temporal lobe bounded by the lateral fissure. Adapted from [3].

Fig-4: Parts of frontal lobe: The area corresponding to prefrontal cortex with dorsolateral prefrontal cortex (dlPFC) and a more caudal part consisting: superior, middle, and inferior frontal gyrus (F1, F2, and F3 respectively). The region associated with motor functions (M1). The medial view of the frontal lobe is also shown on the right with regions more intimately related to reflective and stimulus-driven inputs. Adapted from [3].

References
[1]  Figure 17-2 (p.320), 17-3 (p.321), and 17-5 (p.325). In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[2]  Chapter 3 - Structure of The Nervous System. In Carlson, Neil R. (2013). Physiology of Behavior 11e, Pearson Education.
[3]  David, C. L., et. al. (2010). The Brain and Behavior: An Introduction to Behavioral Neuroanatomy, 3e. Cambridge Press.

Basal Ganglia & Cerebellum - a brief overview

The previous blog post talked about the "hierarchy" of the sensorimotor system, ranging from the highest order of the brain (cerebral cortex) down to the brainstem and the spinal cord. There are two more parts of the CNS that are essential in motor control and we'll discuss them here.

Fig-1: The position of the cerebral cortex, basal ganglia, brainstem, and cerebellum in the motor hierarchy with ways how they influence each other. Both the corticostriatal loop and the corticopontine-cerebellar go through the thalamus.

Outputs from the motor cortex are connected to several subcortical nuclei called the basal ganglia (BG) and the cerebellum. These two compartments are known to influence and modulate movement performance such as accuracy and timely execution. Basal ganglia are especially known to give Go/No-Go signal to the cortex. The role thalamus is particularly essential to convey the information back to the cerebral cortex from the corticostriatal and the corticopontine-cerebellar loop. To complete the topic, it is worthwhile to look at the left diagram.

What are Basal Ganglia?
They are essentially a group of subcortical motor nuclei that include:
(1) The striatum, comprising the caudate nucleus & putamen. They form input channels to BG.
(2) The globus pallidum structures: external (GPe) and internal (GPi) segments.
(3) Substantia nigra at the base of the midbrain.
(4) Subthalamic nucleus (STN), located below or ventral to the thalamus.

The striatum is located at the base of the forebrain lateral to the thalamus and is separated by the internal capsule into the caudate and putamen internally. The structure is 95% composed of a specific type of GABAergic neurons called the medium spiny neurons. Depending on the location, these neurons express different dopaminergic receptors (D1 or D2). Substantia nigra contains two distinct divisions. First, the more medial pars compacta (SNpc) contains dopaminergic neurons that send projections to the striatum. Second, the more lateral pars reticulata (SNpr) contains GABAergic neurons. Together with GPi, SNpr is considered the BG output channels.

Refer to the diagram shown in Fig-2. The concept of Go/No-Go comes from the fact that basal ganglia are able to enhance or inhibit a movement through the influence of two major pathways: the direct (solid lines) and indirect pathways (dotted lines). Specifically:

• Excitatory inputs from the cortical areas increase the inhibitory signal to GPe, causing a decrease in inhibitory activity to STN. Therefore, GPi will be more excited and then send more inhibition to the thalamus. In turn, cortical areas receive less excitation. This is the indirect pathway.
• D1 and D2, two dopaminergic receptors in the striatum are able to maintain balance so that the level of excitation is not out of order. In Parkinson's Disease patients, these receptors are disrupted by the damage to the substantia nigra pars compacta. As a result, there will be no inhibitory control for both GPi and GPe. An overproduction of inhibition causes thalamus to produce less excitatory signals back to the cortex. Muscles and posture become more rigid. 
• These excitatory input signals from the cortex are able to inhibit GPi through the direct pathway. As a result, it brings less inhibition to the thalamus, bringing more excitation to the cortex. Thus, projections back to the cortex have to go through the thalamus. Outputs from the GPi also go to the brain stem. 
• More recently, scientists have shown direct projection from the frontal cortex to STN that bypasses the striatum called the hyperdirect pathway. Thus, this pathway is also independent of D1/D2 influence. The exact function is still debatable.

Fig-2: The cortico-striatal loop showing indirect (dotted lines), direct pathway (solid lines), and hyper direct pathway. 

The BG receive most of their inputs from the cerebral cortex, notably the primary motor cortex, M1. And as mentioned, they also receive dopaminergic inputs from the SNpc. This has a strong implication; it means that the cortical information coming from the cerebral cortex can be modulated by the dopaminergic system. The way BG influence movement can be seen by studying two main motor pathways, i.e. direct and indirect pathways. Both pathways carry projections out through the GPi (globus pallidus interna) as the exit channels. Neurons from these output channels project back to the cerebral cortex and the brainstem through the ventromedial thalamus. The increased activity in one pathway will reduce movement execution, while the other, increase it. Probably, insights on the role of BG to movements come primarily from the studies with Parkinson's Disease patients.

Fig-3: The anatomical divisions of Basal Ganglia and Cerebellum, taken from [1, 2].

What is Cerebellum?
The cerebellum is located posterior to the brainstem. It is smaller than the 'big brain', but contains almost double the number of neurons in it. The cerebellum exerts influence on the ipsilateral side of the body but contralateral to the motor cortex. Cross-sectionally, the cerebellum can be divided into:
(1) Outer gray matter: contains a repeated pattern of circuitry; see below.
(2) The inner white matter with 4 pairs of output nuclei.
(3) Cerebellar peduncles: like highways connecting the cerebellum and the rest of the brain.

White matter nuclei of the cerebellum are the fastigial, the anterior and posterior interposed, and the dentate nuclei. The inputs to the cerebellum are conveyed primarily through the inferior and middle cerebellar peduncles, whereas the outputs are conveyed primarily through the superior cerebellar peduncle. Like the cerebral cortex with its four lobes, we traditionally divide the cerebellum into four divisions: the vermis, intermediate zone, lateral hemisphere, and the flocculonodular zone; the areas best seen if we unroll the cerebellum.

The cerebellum is intimately connected with the motor nuclei in the brainstem, cortical areas, and the thalamus. Frontal motor and parietal lobules are the principal cortical inputs to the cerebellum (Glickstein, 1980s). Refer to my diagram below. Based on the functional circuitry, there are 3 different divisions of the cerebellum:

1. The vestibulocerebellum regulates balance during stance and gait and controls eye movements. It has afferent connections to the vestibular system.
2. The spinocerebellum regulates movement execution of the body and limbs. This is achieved based on somatosensory afferents from distal and proximal limbs, trunk, and other body parts from the spinal ascending tracts. It also receives sensory information from the audio-visual and face areas. Adrian & Snider (c. 1940) found that there is a somatotopic map represented in the area of the vermis and paravermis. Outputs from interposed nuclei are connected to the lateral descending tracts, whereas fastigial nuclei to the more ventromedial tracts. Spinocerebellar circuits modulate movements by monitoring incoming sensory inputs and perform the online adjustment. 
3. The cerebrocerebellum is involved in skilled, timely, and accurate movement planning. It is thought that this area involves cognitive functions. Consistent with this notion, it is the most extensive area in humans, more than that in monkeys. It has direct connections with the motor cortex through pontine nuclei that loop back to the cerebral cortex through the thalamus. 

Fig-4: Summary of 3 functional pathways of the cerebellum shown with their INPUT and OUTPUT connections. 

Cerebellar synaptic organization
The cerebellar gray matter layer contains an intricate, repeated pattern of 'computational' circuitry that is shown in Fig-5. There are two main axons of cerebellar inputs: mossy fibers and climbing fibers. These two types of fibers provide a strong excitatory influence on the cerebellum.

1. Mossy fibers carry information through two pathways. First, direct projections from the spinal cord such as somatic information from skin and muscles. The projections are collectively known as spinocerebellar tracts. Second, indirect projections by going through different brainstem nuclei, e.g. pontine nucleus and reticular formations. Mossy fibers influence Purkinje cells indirectly through inhibitory cerebellar interneurons.
2. Climbing fibers carry information strictly from the inferior olive nucleus located at the midbrain. This structure, in turn, receives axons from the vestibular nuclei, tectum, dorsal column nuclei, and cortex. Climbing fibers make direct contact with the Purkinje cells. Unlike mossy fibers, climbing fibers have the capability to elicit complex spikes. Scientists believe that these spikes occur mostly when there is sensory prediction error e.g. during learning or adaptation.

Purkinje cells are the only output from the cerebellar cortex to deep white matter. They have massive dendritic branching, allowing multiple synaptic inputs, and carry post-synaptic inhibitory (GABAergic) outputs to the cerebellar nuclei.

Deep cerebellar nuclei always yield excitatory outputs to the thalamus before sending the flow back to the cerebral cortex. However, this excitatory state is modulated by two things: direct influence from mossy/climbing fibers and from the Purkinje cells.



Fig-5 Synaptic organization within the cerebellum. There are multiple loops within the circuitry. The dentate nucleus is the largest cerebellar nuclei that influence the motor cortex via the thalamus. Thus, the cerebellum is able to influence voluntary movement.



References
[1]  Chapter 42 - Cerebellum. In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[2]  Chapter 43 - Basal Ganglia. In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[3]  Chapter 8 - Control of Movement. In Carlson, Neil R. (2013). Physiology of Behavior 11e. Pearson Education.

The Somatosensory System - a brief overview

Principles of Sensory Coding

The sensory system is a part of our nervous system that processes sensory information. Through the five sense-doors, it is responsible for giving direct representations of the outside world. Some key principles govern the way our sensory system works. First, the sensory system extracts sensory information arriving based on the type of stimulus (modality), location, intensity, and duration. Second, the arriving stimulus creates certain perceptual experiences within us. The conversion of stimulus information into neural signals by the sensory system is called sensory coding. Arriving external stimuli will be captured as energy by specialized peripheral "sensors" called receptors. These sensitive organs can be found in all five senses: eyes, ears, nose, tongue, and bodily receptors. The basic sensory modalities include light, sound, smell, taste, temperature, and pressure. Law of receptor specificity says that different nerve fibers are dedicated to different sensory modalities. 

• Location coding: we are aware of a specific site of touching or pressure (location of the stimulus) as it impinges a specific receptor on the skin. Such receptor is broadly called the receptor field. This receptor field in turn makes a specific connection in the brain such that different areas in the brain are stimulated. Location coding is not preserved in the chemosensory modality. 
• Intensity coding: the greater the stimulus intensity beyond a certain threshold of detection (see: Psychophysics), the greater the output of the receptor. More importantly, the intensity of a stimulus is coded in frequency terms -- the greater the stimulus intensity, the greater the discharge rate of action potential. However, other non-sensory factors are able to influence this frequency: fatigue, motivation, etc. 
• Duration coding: our awareness stay as long as the stimulus exists. To some senses, the awareness of a stimulus may decline over time, a process called adaptation, and it is caused by the way ion channels work. E.g. we perceive the cushion-like feeling when we first sit on the chair, but that awareness gradually disappears. 
• From the receptors, signals are transmitted through several anatomically distinct pathways following a concept of parallel pathways. Parallel processing is an important feature of hierarchical sensory processing. Brain compartments that process sensory information have an orderly, topographic, structured representation. The sensory systems do not enjoy equal representation in the brain (e.g. the somatotopic map of touch perception). 

The visual system, centered on the Occipital Cortex, is arguably the most dominant percept. Among the senses, however, the somatosenses or the perception of 'body' is intimately related to the motor cortex to plan and guide goal-directed movement. This post attempts to summarize their neural substrates and behavior.

There are three types of somatosenses based on the modality, the type of stimuli our brain perceives. First, the mechanoreceptors detect touch, pain, and temperature stimuli, and are embedded inside the dermal layer of the skin. A wide variety of receptors are able to detect vibration, stretch, pressure, shape, and texture. The proprioception & kinesthesia, embedded mainly in the joints and muscles, detect the position and movement of the trunk and limbs. And lastly, the senses of the internal organs in the body detect pain sensation or discomfort.

Proprioception is one of the core themes in my lab. Originally thought only to be sensed by certain sensory neurons in the muscle, proprioceptive information is also received by other mechanoreceptors in the skin and muscles. There is a set of specialized sensory neurons coming from the muscles. Embedded deep inside the extrafusal fibers is a set of muscle spindles that carry Type Ia and II sensory neurons. They encode muscle length or stretch. When the muscles contract, however, they lose sensitivity and fire less. It is the gamma motor neurons that increase or offset the loss of sensitivity by introducing tension to the muscle spindle. Type Ia neurons, in particular, are sensitive to the change in the stretch over time or velocity. Type Ib sensory neurons originate in the tendon organ that encodes muscle tension, but not stretch or length. Microelectrode recording is able to distinguish their discharge pattern in response to a certain behavior manipulation.

Fig-1:  Major ascending pathways; taken from [3].        

The Ascending Pathways
The spinal cord plays a critical role as it contains massive highways from and to the brain. Cross-sectionally, the spinal cord is divided into the core grey matter (H-shaped butterfly) surrounded by white matter. The ventral portion of the grey matter contains cell bodies of alpha motor neurons. The dorsal portion contains sensory axons and cell bodies of interneurons. The spinal cord is important for short-latency reflex.

The spinal cord serves as the base in the motor hierarchy but it is the first station of the sensory inflow to the brain. 

Sensory information from the trunk and limbs enters the spinal cord and travels up to the cerebral cortex through the thalamus, the ventral-posterior-lateral nucleus. 

The pathways called the ascending sensory pathways, work in parallel to ensure timely information delivery. The cell bodies of the sensory receptors are collectively called the dorsal root ganglion.

Two sensory pathways are present depending on the type of modality. The more precise receptors (touch, kinesthesia) ascend to the medulla and the thalamus through dorsal columns. The axons cross at the medulla forming the medial lemniscus to the opposite side of the brain, just like the descending motor pathways and hence contralateral in nature. The second pathway is dedicated to more poorly localized percepts such as pain and temperature. Upon entering the gray matter, the axons immediately cross and form the spinothalamic tract up to the thalamus. This tract is part of the bigger anterolateral pathways.

Thalamus as a Relay System
Thalamus is an important structure near the middle of the cerebral hemisphere, medial and caudal to the basal ganglia. It has two lobes in both left/right hemispheres and receives information from one part of the central nervous system (e.g. basal ganglia, cerebellum, motor cortex) and sends it to the other region through projection fibers. It is an essential link between sensory receptors and the cortex for all modalities except olfaction. This oval-shaped structure is situated bilaterally and consists of several distinct nuclei.

There are two types of thalamic nuclei in the thalamus: specific and non-specific. The name arises due to the way the nucleus is related to different brain regions. The non-specific nuclei, mainly in the internal medullary lamina, possess complicated input-output connections and does not bear selectivity or specificity to a certain cortical region or cortical function. The specific thalamic nuclei, whose outputs are excitatory (glutamatergic system), consist of four main divisions:

1. Anterior division: consists only of one nuclei and is linked to the mammillary bodies (part of the hypothalamus) and hippocampal formation, the cingulate and frontal lobe.
2. Medial division: it is connected to the basal ganglia, amygdala, and the midbrain, been implicated in memory.
3. Ventral division: the division that is very important for sensorimotor-related behavior. The ventro-anterior and ventro-lateral nuclei send information from the basal ganglia and cerebellum to motor cortex. We just mention the area that's involved in sending somatosensory information to S1. 
4. Posterior division: this area is mainly for the auditory (medial geniculate nucleus) and visual system (lateral geniculate nucleus); there is also the pulvinar nuclei that carry various functions and are interconnected to the parietal and occipital lobe.

The thin outer layer of the thalamus, called the reticular nucleus, is thought to provide inhibitory feedback. This means that the thalamus is not merely a congregation of relays but able to perform some information processing in the nuclei.

The Somatosensory Cortex
Axons in the ventral-posterior-lateral nucleus terminate primarily in the postcentral gyrus, or more popularly now as the primary somatosensory cortex or S1. It is situated between the central sulcus and postcentral sulcus, caudal to the primary motor cortex. We gain insights into this area by using the same electrical stimulation technique similar to the ones used in cortical motor experiments. Penfield found that these neurons are sensitive to tactile stimulation of the skin surface. Other scientists e.g. Woolsey, Kaas, etc. performed similar experiments on monkeys.

Like the primary motor cortex, the bodily representation in S1 is arranged in an orderly fashion or somatotopic. It turns out that the topography is not simple and the postcentral gyrus is further subdivided into Area 3a, 3b, 1, and 2 (correspondingly BA-3a/b, BA-1, and BA-2). Area 3 processes the basic somatosensory information and is arguably the only S1-proper as it receives the most projections from the thalamus. Neurons in BA-3a/b are found to have the smallest receptive fields. So what are the functional divisions of the somatosensory cortex?

• Proprioceptive sensory information from the muscles and joints is represented in Area 3a.
• Cutaneous and tactile information is represented in Area 3b.
• Area 3a/3b sends projections to Area 1 where higher-order processing takes place.
• Lastly, Area 2 is where information from Area 1 is fused with information from muscles and joints to facilitate richer tactile recognition related to grasping such as size and shape, and joint information while moving. The cells have the largest receptive fields.

Fig-2:  The primary somatosensory cortex; adapted from [2]. Note how the coronal section reveals BA-4 as well.

The cortical-body mapping is represented by the homunculus map. Just like M1, the larger the area in S1 of a certain body map, the greater the number of 'computational efficiency' power involved. For example: our highly discriminative sense of touch in the index finger is due to the large area in S1 dedicated to processing somatosensory stimuli from this part of the body. By virtue of synaptic plasticity, it is important to note that the mapping can be modified by experience. Experiments in monkeys (e.g. Jenkins and Merzenich, et al., 1990) focusing on tactile sensation have shown that the cortical representation of the digits expands after repeated training or usage of that digits.

What's next? S1 and beyond

From the primary area, somatosensory information is transmitted to secondary areas such as the second somatosensory area (SII), insula, and parietal association areas. Okie, honestly their functionalities are rather vague and mixed. The second somatosensory cortex (SII, or S2) is located on the upper ceiling of the lateral fissure, an area called the parietal operculum. It receives inputs from all four divisions of the primary somatosensory cortex. These inputs appear to be crucial for if they are removed, SII will not elicit any response to tactile stimulation. Removal of SII neurons, on the other hand, do not influence neural response in S1. SII has projections to the insular cortex and temporal areas associated with tactile memory. One function of the insular cortex in body awareness is in understanding and judging pain.

The somatosensory cortex is also tightly linked to other, more posterior areas in the parietal lobe. Areas such as BA-5 and BA-7 receive inputs from S1 and are important in guiding movements, i.e. reaching and grasping. However, to make movements, we need visual inputs and proper decision-making. The integration of visual and somatosensory codes occurs in the posterior parietal cortex and it is often called the somatosensory association areas. The areas send projections to the frontal lobe, parahippocampal region, cingulate gyrus, etc. for higher-order cognition and learning. These areas integrate sensory information of multiple modalities and hence they are multimodal.

Fig-3:  Relationship between S1 and the association sensory cortex of the brain; taken from [1]. It can be seen that neurons in S1 project to M1, and the so-called secondary motor and somatosensory cortices.

Final remark: the homunculus

Homunculus describes the somatotopic mapping of afferent and efferent projections that are responsible for our movement and bodily senses. Typically, a large area of the body in the brain corresponds to higher processing resources in the brain (and vice versa). Humans are well-known to possess good fine motor skills as shown by the large hand representation in the motor and somatosensory cortices. See below.

Fig-4: Homunculus of the somatosensory (afferent) and motor (efferent) projections.

As mentioned, the primary motor cortex (M1) receives a large projection from S1. Both areas are also organized in an orderly somatotopic fashion. One advantage of having the motor and somatotopic maps in close proximity (i.e., on either side of the central sulcus) is that it permits a more precise registration in the connectivity. The specificity in terms of bodily representation between M1 and S1 is reflected by the homotopic connection.

This connection is understandable given how closely the two systems must cooperate when we physically interact with an object. Indeed, the projections of S1 to M1 are organized in a homotopic fashion—that is, a given part of the motor cortex receives projections from the same part on the body map of the somatosensory cortex. Such interaction requires processes that rely on feedback signals from tactile receptors in the skin and proprioceptive receptors in the muscles.

References

[1]  Chapter 18 - The Functional Organization of Perception and Movement. In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.

[2]  Figure 20-1 (p.384) and Figure 23-1 (p.453). In Kandel E.R. et. al. (2000). Principles of Neural Science 4e, McGraw-Hill.
[3]  Chapter 7 - Audition, Chemical, Body Senses. In Carlson, Neil R. (2013). Physiology of Behavior 11e. Pearson Education.