The limbic system has been traditionally described as involving a complex network of neural circuitry composed of the parahippocampal gyrus, the cingulated gyrus, the subcallosal gyrus (which is the anterior and inferior continuation of the cingulate gyrus), the hippocampal formation (which includes the hippocampus proper, the dentate gyrus, and the subiculum), various nuclei of the septal region, the nucleus accumbens (which is an extension of the caudate nucleus), neocortical areas such as the orbital frontal cortex, subcortical structures such as the amygdala, and various nuclei of the hypothalamus (Iversen et al. 2000) (Fig. 6.2).

Figure 6.2 Traditional limbic structures. The traditional components of the limbic system and the projections thought to exist between the anatomical components are illustrated. The projections shown are probably incomplete as the limbic system, like most other functional neural circuits, functions as a unit, utilising a variety of components simultaneously or independently as necessary.

The hypothalamus contributes to limbic system function primarily through controlling influences on the pituitary gland. Neurons in the medial basal region of the hypothalamus release peptide neurohormones that act as stimulators or releasing factors that act on the cells of the anterior pituitary gland or adenohypophysis. The pituitary cells then release a variety of hormones including luteinizing hormone (LH), the growth hormone (GH) somatotrophin, adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), and prolactin. Axons of neurons in the supraoptic and paraventricular nuclei release the neurohormone oxytocin and the antidiuretic hormone vasopressin (Fig. 6.3).

Figure 6.3 Hormones of the pituitary gland. The relationship between the hypothalamus, the pituitary gland, and the hormones secreted from the pituitary gland is illustrated. The pituitary gland is often referred to as the ‘master gland’ of the endocrine system because it coordinates many functions of the other glands. The endocrine system itself consists of a group of organs whose main function is to produce and secrete hormones directly into the blood that act to control a variety of functions all over the body. The major organs of the endocrine system are the hypothalamus, the pituitary gland, the thyroid gland, the parathyroid glands, the islets cells (Beta cells) of the pancreas, the adrenal glands, the testes, and the ovaries. The hypothalamus releases messengers that act as releasing or stimulating agents on the pituitary as well as inhibiting factors that inhibit the activation or release of certain hormones of the pituitary. Not all endocrine glands are under the sole control of the pituitary. Some glands such as the insulin-secreting (Beta) cells of the pancreas also respond to local levels of glucose and fatty acids; the parathyroid glands also respond to local concentrations of calcium and phosphate in the blood; and the adrenal medulla or the adrenaline-producing cells of the adrenal glands also respond to direct stimulation from the sympathetic nervous system.

The hypothalamus also functions as a communication relay by funnelling information from the cortex via the cingulate gyrus, to the hippocampal formation, where the information is processed and reciprocally fed back to the cingulate gyrus via the mammillary bodies and anterior thalamic nuclei.

Neurons in a variety of hypothalamic nuclei also project to the intramedial lateral (IML) cell columns of the spinal cord grey regions where they modulate the activity of the preganglionic neurons of the sympathetic nervous system, which control a variety of functions including blood flow to virtually all areas of the body. This pathway is important in modulating blood flow to various muscle groups and organs including the brain, prior to and during movement. The control of the blood flow to the hypothalamus arises from postganglionic sympathetic neurons located in the superior cervical ganglion, which are under the influence of the hypothalamus itself (Fig. 6.4).

Figure 6.4 Control of blood flow to the hypothalamus. The cells of the hypothalamus project directly to the presynaptic sympathetic neurons in the intermediolateral (IML) cell column of the spinal cord. These neurons project to the postsynaptic cells of the sympathetic system located in the superior cervical ganglia. The axons of these neurons follow a variety of blood vessels into the skull and innervate the blood vessels supplying the hypothalamus.

The limbic system is deeply involved in the creation of motivational states or drives that modulate the central integrative states of neurons in wide-ranging areas of the central nervous system (CNS) that produce a variety of behavioural responses such as movement, temperature regulation, active procurement of food, sexual drive, emotional context, and curiosity (Swanson & Mogenson 1981; Brooks 1984; Kupfermann et al. 2000).

Motivational drives produced in the limbic system appear to be the products of integrated sensory and emotional cues, which have been triaged into some order of importance that results in the activation of the appropriate areas of cortex to a readiness or activation mode. Thus, through motivational activation from the limbic system, the appropriate areas of cortex increase their central integrative state to a state of awareness, looking for something about to happen such as a change in posture or a change of emotional state.

The transition from motivation to the initiation of movement involves pathways from multiple premotor regions of the cortex to the motor regions of cortex.

The majority of the neurons in the inferior and posterior regions of the intraparietal sulcus (Brodmann area 7) show an early response to sensory cues that relate to the execution of movement (Mountcastle et al. 1975). Smaller numbers of neurons in area 7 exhibited more complex response patterns, where activation only occurred in specific situations where a number of variables were met simultaneously, e.g. sight of food and the presence of hunger (Fig. 6.5).

Figure 6.5 Complex stimulus firing patterns demanded by some neurons before firing. (A) Although hunger stimulus is firing on this neuron, either other inputs are not sufficient to stimulate an action potential or they are inhibitory to the formation of an action potential threshold stimulus. No action potential is generated. (B) All conditions are met in this neuron and an action potential fires.

This type of processing suggests that motivational drives received from the limbic system are not blindly obeyed but are first presented to the association areas of premotor and parietal cortex, where a rudimentary form of judgment as to the appropriateness of the behaviour required is made.

The judgement system seems to consist of a series of complex gate systems of ‘and’ or ‘or’ gates that are both involved directly in gating inputs and are indirectly gated themselves by being involved in the more complex array of interactions involved in the complete execution command required. This complex array of gated pathways in the association cortex projects directly to the motor cortex via association fibres as well as to the striatum and pontine nuclei. These projections to the striatum and pontine nuclei further project to other areas of the nervous system and form indirect pathway projection loops from the association cortex to the motor cortex (Rolls 1983; deZeeuw et al. 1997).

The first indirect projection loop involves the striatum (caudate nucleus and putamen), whose output nuclei the globus pallidus pars interna projects through the anterior division of the thalamic fasciculus to the pars oralis area of the ventral lateral and ventral anterior thalamic nuclei. Neurons of the ventral lateral thalamic nuclei project their axons to the ipsilateral motor, premotor, and parietal cortical areas (Fig. 6.6).

Figure 6.6 The first indirect corticostriatal–thalamocortical loop.

The second indirect projection loop involves projections to the ipsilateral pontine nuclei via the corticopontine projection fibres, which in turn project to two output nuclei of the contralateral cerebellum via the pontocerebellar fibre system. These deep cerebellar nuclei, the dentate, and the interposed nuclei (emboliform and globose nuclei) then project to the contralateral pars caudalis area of the ventrolateral thalamic nuclei via the posterior division of the thalamic fasciculus. Neurons of the ventrolateral thalamic nuclei project their axons to the ipsilateral motor, premotor, and parietal cortical areas (Fig. 6.7).

Figure 6.7 Corticopontocerebellulo-thalamic loop.

To further complicate matters, the major indirect pathways from the premotor to the motor cortex involving the basal ganglionic and pontine-cerebellar loops are not equivalent in the cerebral cortical areas from which they receive inputs nor the projections to the cortex that arise from them.

The basal ganglionic loops involve two distinct pathways. The first involves input pathways to the caudate nucleus (see Fig. 6.6); the second involves input pathways through the putamen (see Fig. 6.7). For instance, the caudate nuclei receive inputs from many areas of cortex including the association regions of the frontal, parietal, and temporal lobes. Most of the afferent or return projections from this loop arise from the globus pallidus pars interna of the basal ganglia and project to the ventral anterior nuclei of the thalamus. Neurons in the ventral anterior nuclei of the thalamus project to the premotor cortex (Brodmann area 6).

The second pathway of the basal ganglionic loop involving the putamen receives the majority of its input from the sensorimotor cortex (Brodmann areas 3, 2, 1, and 5) and projects via the globus pallidus pars interna to the ventrolateral nuclear group of the thalamus. The ventrolateral group of thalamic neurons then project to premotor areas including Brodmann area 6 (Delong et al. 1983). This projection loop is very important for basal ganglionic modulation of motor cortical output since the basal ganglia do not possess direct projections from the thalamus to primary motor cortex (Schell & Strick 1984).

The pontine and cerebellar loops receive the majority of their inputs from the primary motor (area 5), somatosensory areas (areas 4, 3, 2, and 1), and some input from association and visual areas (areas 17 and 18). Very little input to the pontine and cerebellar loops comes from high-level association areas (Rolls 1983).

All of the indirect loops described above contain reciprocal innervation pathways above the thalamus (thalamus to cortex, cortex to thalamus) and only unidirectional pathways below the thalamus (basal ganglia to thalamus, pontine nuclei to thalamus) (Sherman & Guillery 2001) (Fig. 6.8). In fact, the thalmocortical projections form a loop in which the ‘feedforward’ portion is part of the classic pathway relaying sensory information to the cortex and the ‘feedback’ portion is composed of cortical control or modulation over thalamic operation. This feedback control can be either excitatory or inhibitory depending on the central integrative state of the cortex and is modulated itself by sensory input from the thalamus (Llinas 1991; Destexhe 2000). This results in a variety of intrinsic thalamocortical and corticothalamic oscillations that can be observed via electroencephalograph (EEG) and quanitative electroencephalograph (qEEG) recordings over the cortex (Destexhe & Sejnowski 2003).

Figure 6.8 All of the indirect loops described contain reciprocal innervation pathways above the thalamus (thalamus to cortex, cortex to thalamus) and only unidirectional pathways below the thalamus (basal ganglia to thalamus, pontine nuclei to thalamus).

To summarise thus far using our example of a pinch grasp of an object between the finger and thumb, the neural activity involved depends on the motivation for the movement in the first place. Is the object food and is the subject hungry? Is the subject just curious as to what the object is? The pathways through which movement is initiated depend on a number of variables such as prelearning of movement components, the relevance and importance of the movement at the time, and whether a variety of movement choices must be considered. Once initiated, the plastic nature of the system provides a multitract system (basal ganglionic and pontine/cerebellar) which can consider a multitude of physical variables as well as the initial motivation in order to complete the desired movement.

Once the ‘what am I going to do’ instructions have been established, integrated, and weighed with respect to relevance and appropriateness by the limbic system and high-level association cortex, the high-level areas of the hierarchy, the neural information is transferred to the middle layers of the hierarchy, which involves the creation of the ‘how am I going to do it’ outflow.

Formulation of the ‘how to’ instructions involves the premotor cortex (area 6), which acts as an organiser for the principal output area, the primary motor cortex (area 4) (Brooks & Thach 1981).

Instructions for acts of different complexity enter the middle-level areas via separate routes. For example, motor programmes for complex movement patterns enter from the caudate circuit of the basal ganglia, whereas instructions for less complex actions enter the premotor area via the putamen circuit of the basal ganglia as well as the lateral cerebellum pontine nuclei circuit (Brooks 1984).

Changes in neuron potentials have been recorded over the motor cortex 800 ms before the onset of voluntary movement (Krakauer & Ghez 2000). In this period before the onset of movement the higher centres seem to be presetting the neuron response patterns in relation to the specific preset programmes that specify the intended movement. The set of preset programmes that describe a specific movement are referred to as a motor set.

Thus, the various levels of instruction from the basal ganglia, the cerebellum, and transcortical input from association areas integrate to prepare the motor cortex prior to the initiation of movement to ensure the correct motor sets will be initiated at the right time and in the right sequence.

Most probably, cortical motor columns are directionally oriented so that increasing the central integrative state (CIS) results in an increased probability that the preferential direction represented by the column will be reproduced by the somatotopic corticospinal projections to the appropriate motor neurons. When a particular movement direction is desired, the firing frequency in the appropriate cortical column which represents the desired direction increases. Interneurons contained within the desired cortical column that project to antagonist motor columns are also brought to threshold and fire inhibitory barrages. Individual neurons do not seem to encode direction individually but require a population of neurons firing in a coordinated fashion to generate a desired directional movement. The end result of this activity is that the alpha motor neurons in the spinal cord that represent the desired direction have an increased probability of reaching activation threshold and those representing the opposite direction have a decreased probability of reaching activation threshold. The corticospinal tract is only one of several tracts that synaptically modulate the alpha motor neurons to determine their CIS. It may be recalled that dorsal root ganglion cells arising from the tendons and the muscle spindles also project either directly or indirectly to modulate the CIS of the alpha motor neurons, as do neurons in the reticular formation and vestibular areas. It has been estimated that approximately 10 000 synapses, some inhibitory and some excitatory, converge onto each alpha motor neuron. The cumulative effect of all of this synaptic activity largely determines the CIS of the neuron at any given moment. Other factors influencing the CIS include the nutritional, biochemical, and oxygen status of the neuron.

The timing and the pattern of activation of the desired muscles during movement are largely controlled by the cerebellum.