Mitral cell axons run centrally in the olfactory tract (Figure 34.2). The tract divides in front of the anterior perforated substance into medial and lateral olfactory striae.

Figure 34.2 Brain viewed from below, showing cortical olfactory areas.

The medial stria contains axons from the anterior olfactory nucleus, which consists of multipolar neurons scattered within the olfactory tract. Some of these axons travel to the septal area via the diagonal band (see later, under Limbic system). Others cross the midline in the anterior commissure and inhibit mitral cell activity in the contralateral bulb (by exciting granule cells there). The result is a relative enhancement of the more active bulb, providing a directional cue to the source of olfactory stimulation.

The lateral olfactory stria terminates in the piriform lobe of the anterior temporal cortex. The human piriform lobe includes the cortical part of the amygdala, the uncus, and the anterior end of the parahippocampal gyrus. The highest center for olfactory discrimination is the posterior part of the orbitofrontal cortex, which receives connections from the piriform lobe via the mediodorsal nucleus of the thalamus.

The medial forebrain bundle links the olfactory cortical areas with the hypothalamus and brainstem. These linkages trigger autonomic responses such as salivation and gastric contraction, and arousal responses through the reticular formation.

Points of clinical interest are mentioned in Clinical Panel 34.1.

Clinical Panel 34.1 Olfactory disturbance

A routine test of olfactory function is to ask the patient to identify strong-smelling substances such as coffee and chocolate through each nostril in turn. Loss of smell, or anosmia, may not be detected by the patient without testing if it is unilateral. If it is bilateral, the complaint may be one of loss of taste because the flavor of foodstuffs depends on the olfactory qualities of volatile elements; in such cases, the four primary taste sensations (sweet, sour, salty, bitter) are preserved. Unilateral anosmia may be caused by a meningioma compressing the olfactory bulb or tract, or by a head injury with fracture of the anterior cranial fossa. Anosmia may be a clue to a fracture, and should prompt tests for leakage of cerebrospinal fluid into the nasal cavity.

Olfactory auras are a typical prodromal feature of uncinate epilepsy (see Clinical Panel 34.3).

Limbic System

The limbic system comprises the limbic cortex (so-called limbic lobe) and related subcortical nuclei. The term ‘limbic’ (Broca, 1878) originally referred to a limbus or rim of cortex immediately adjacent to the corpus callosum and diencephalon. The limbic cortex is now taken to include the three-layered allocortex of the hippocampal formation and septal area, together with transitional mesocortex in the parahippocampal gyrus, cingulate gyrus, and insula. The principal subcortical component of the limbic system is the amygdala, which merges with the cortex on the medial side of the temporal pole. Closely related subcortical areas are the hypothalamus, reticular formation, and the nucleus accumbens. Cortical areas closely related to the limbic system are the orbitofrontal cortex and the temporal pole (Figure 34.3).

Figure 34.3 Medial view of cortical and subcortical limbic areas. MDN, mediodorsal nucleus of thalamus.

Figure 34.4 is a graphic reconstruction of mainly subcortical limbic areas.

Figure 34.4 Three-dimensional computerized reconstruction of postmortem brain showing components of the limbic system in relation to the ventricular system.

(Excerpt of figure from Kretschmann and Weinrich, 1998, with kind permission of the authors and the publisher.)

Parahippocampal gyrus

The parahippocampal gyrus is a major junctional region between the cerebral neocortex and the allocortex of the hippocampal formation. Its anterior part is the entorhinal cortex (area 28 of Brodmann), which is six-layered but has certain peculiar features. The entorhinal cortex can be said to face in two directions. Its neocortical face exchanges massive numbers of afferent and efferent connections with all four association areas of the neocortex. Its allocortical face exchanges abundant connections with the hippocampal formation. In the broadest terms, the entorhinal cortex receives a constant stream of cognitive and sensory information from the association areas, transmits it to the hippocampal formation for consolidation (see later), retrieves it in consolidated form, and returns it to the association areas where it is encoded in the form of memory traces. The fornix and its connections form a second, circuitous pathway from hippocampus to neocortex.

The hippocampal complex (or hippocampal formation) comprises the subiculum, the hippocampus proper, and the dentate gyrus (Figure 34.5). All three are composed of temporal lobe allocortex which has tucked itself into an S-shaped scroll along the floor of the lateral ventricle. The band-like origin of the fornix from the subiculum and hippocampus is the fimbria. The hippocampus is also known as Ammon’s horn (after an Egyptian deity with a ram’s head). For research purposes, it is divided into four cornu ammonis (CA) zones (Fig. 34.6A).

Figure 34.5 Hippocampal formation. (A) View from above. (B) Enlargement from (A) showing the entorhinal cortex and the three component parts of the hippocampal formation.

The principal cells of the subiculum and hippocampus are pyramidal cells; those of the dentate gyrus are granule cells. The dendrites of both granule and pyramidal cells are studded with dendritic spines. The hippocampal complex is also rich in inhibitory (GABA) internuncial neurons.

It should be mentioned that in general discussions related to memory, it is customary to use the term ‘hippocampus’ as synonymous with ‘hippocampal complex’.

Connections

Afferents

The largest afferent connection of the hippocampal complex is the perforant path, which projects from the entorhinal cortex onto the dendrites of dentate granule cells (Figure 34.6B). The subiculum gives rise to a second, alvear path which contributes to a sheet of fibers on the ventricular surface of the hippocampus, the alveus.

The axons of the granule cells are called mossy fibers; they synapse upon pyramidal cells in the CA3 sector. The axons of the CA3 pyramidal cells project into the fimbria; before doing so they give off Schaffer collaterals, which run a recurrent course from CA3 to CA1. CA1 projects into the entorhinal cortex.

Auditory information enters the hippocampus from the association cortex of the superior and middle temporal gyri. The supramarginal gyrus (area 40) transmits coded information about personal space (the body schema described in Ch. 32) and extrapersonal (visual) space. From the occipito-temporal region on the inferior surface, information concerning object shape and color, and facial recognition, is projected to cortex called perirhinal, or transrhinal, immediately lateral to the entorhinal cortex. From here, it enters the hippocampus. A return projection from entorhinal to perirhinal cortex is linked to the temporal polar and prefrontal cortex.

In addition to the discrete afferent connections mentioned above, the hippocampus is diffusely innervated from several sources, mainly by way of the fornix:

• A dense cholinergic innervation, of particular significance in relation to memory, is received from the septal nucleus.

• A noradrenergic innervation is received from the cerulean nucleus.

• A serotonergic innervation enters from the raphe nuclei of the midbrain. The linkage between serotonin depletion and major depression is mentioned in Chapter 26.

• A dopaminergic innervation enters from the ventral tegmental area of the midbrain. The linkage between dopamine and schizophrenia is discussed in Clinical Panel 34.2.

Clinical Panel 34.2 Schizophrenia

Schizophrenia occurs in about 1% of the population in all countries where the prevalence has been studied. It is a heritable illness with around a 10% risk of occurrence if a person’s first-degree relative is affected, and as much as 50% risk of occurrence if both parents or an identical co-twin is affected. Although the onset of illness is typically in early adulthood, there is substantial evidence for neurodevelopmental disturbance in the illness, with increased rates of birth complications, early developmental insults, and childhood social, motor, and academic underperformance in those who later develop schizophrenia. Cognitive dysfunction is present in the illness, but relatively stable throughout life, unlike the progressive dementias.

MRI studies reveal enlargement of lateral ventricles and regionally specific atrophy predominantly affecting frontal and temporal parts of the cortex, the medial temporal lobe, and thalamus. There is a reduction or even a reversal of the usual left–right difference in the size of the temporal plane on the upper surface of the superior temporal gyrus. There is some progression of these neuroimaging abnormalities in the early years of the illness which then plateau. Postmortem studies indicate that the atrophy identified by imaging studies is related to loss of neuropil and reduced neuronal size rather than neuronal loss. No evidence of astrogliosis or of neurodegenerative disease pathology has been identified. Consistent with neurodevelopmental disturbance, underlying the illness are findings of aberrantly located neurons, for example in the entorhinal cortex and in white matter.

The clinical presentation is quite variable but the symptoms and behavioral changes can be categorized into two broad spectra – positive symptoms and negative symptoms.

• Positive psychotic symptoms include hallucinations, delusions, and disorganized thoughts and behavior. Hallucinations are typically auditory (the patient hears voices, which are commonly derogatory in nature and refer to the patient in the third person). Delusions often take a paranoid form, with a belief that the patient is being monitored or the subject of a conspiracy. Other typical delusions include a belief that one’s thoughts and actions are being controlled by an outside agency and that thoughts are not private, but are somehow accessible by other people. Thought processes frequently become disorganized with the normal flow and logic of speech breaking down and in severe cases becoming incoherent. Disorganized behavior includes disinhibited, socially inappropriate behaviour or in some cases physical aggression in response to hallucinations or delusions. Although positive symptoms cause great distress to patients and their families, they are much more responsive to antipsychotic medication treatment than the negative ones, which in the long term are more disabling.

• Negative (deficit) psychotic symptoms refer to an inability to engage in normal emotional and social interactions with people and frequently lead to impaired capacity to self-care. The patient lacks motivation, has little to say, and in conversation rambles from one inconsequential theme to another. There is a loss of emotional responsiveness (flattening of affect), including inability to experience pleasure (anhedonia). Personal hygiene and ability to live independently and manage affairs are often impaired. The negative symptoms appear to be associated with ‘hypofrontality,’ i.e. diminished prefrontal function. Functional imaging studies using fMRI and PET support this idea by demonstrating failure of the normal response of the dorsolateral prefrontal cortex to standard tests of cognitive function.

Medications used to treat psychotic disorders such as schizophrenia are called antipsychotics, neuroleptics or major tranquillizers. All such antipsychotic medications block dopamine D₂ receptors to some extent (e.g. haloperidol or olanzapine). In the normal brain, the D₂ receptors are on spiny (excitatory) stellate cells in the mesocortical projection territory of the ventral tegmental nucleus. D₂ receptors are inhibitory, for one or more of three possible reasons noted in Chapter 8. Interestingly, symptoms closely resembling the positive psychotic ones of schizophrenia may be induced by consuming excessive amounts of dopamine-stimulating drugs such as cocaine or amphetamine (’speed’). Amphetamine is known to increase the amount of dopamine in the forebrain extracellular space (Clinical Panel 34.5). In schizophrenia, dopaminergic overactivity seems not to be a matter of overproduction but of greater effectiveness through an increased number of postsynaptic dopamine receptors on the spiny stellate neurons. (The assistance of Professor Colm McDonald, Department of Psychiatry, NUI, Galway, Ireland is gratefully appreciated.)

References

Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40-68.

Leonard BE. Drug treatment of schizophrenia and the psychoses. In: Fundamentals of psychopharmacology. Chichester: Wiley; 2003:255-294.

Picchioni MM, Murray RM. Schizophrenia. BMJ. 2007;335:91-95.

Efferents

The largest efferent connection is a massive projection via the entorhinal cortex to the association areas of the neocortex. A second, forward projection is the fornix (Figure 34.5A). The fornix is a direct continuation of the fimbria, which receives axons from the subiculum and hippocampus proper. The crus of the fornix arches up beneath the corpus callosum, where it joins its fellow to form the trunk and links with its opposite number through a small hippocampal commissure. Anteriorly, the trunk divides into two pillars. Each pillar splits around the anterior commissure, sending precommissural fibers to the septal area and postcommissural fibers to the anterior hypothalamus, mammillary body, and medial forebrain bundle. The mammillary body projects into the anterior nucleus of thalamus, which projects in turn to the cingulate cortex, completing the Papez circuit from cingulate cortex to hippocampus, with return to cingulate cortex via fornix, mammillary body, and anterior thalamic nucleus (Figure 34.7).

Figure 34.7 The Papez circuit.

1 Backward-projecting neurons in the cingulate gyrus.

2 Projection into the entorhinal cortex.

3 Projection into hippocampus.

4 Fornix.

5 Mammillothalamic tract.

6 Projections from anterior nucleus of thalamus to cingulate cortex.

The term medial temporal lobe is clinically inclusive of the hippocampal complex, parahippocampal gyrus, and amygdala. The term is most often used in relation to seizures (Clinical Panel 34.3).

Clinical Panel 34.3 Temporal lobe epilepsy

Complex focal (partial) seizures are synonymous with temporal lobe epilepsy. The initial event, or aura, may be a simple partial seizure whose electrical activity escapes into the temporal lobe. Many originate in a focus of runaway neural activity within the temporal lobe and spread over the general cortex within seconds to trigger a secondarily generalized tonic–clonic seizure (Figure CP 34.3.1) as mentioned in Chapter 30. Types of temporal lobe auras include well-formed visual or auditory hallucinations (scenes, sound sequences), a sense of familiarity with the surrounding scene (’déjà vu’), a sense of strangeness (‘jamais vu’) or a sense of fear. Attacks originating in the uncus are ushered in by unpleasant olfactory or gustatory auras. Bizzare psychic auras can occur, where the patient has an ‘out of body experience’ in the form of a sensation of floating in the air and looking down at themselves and any others present.

Following accurate localization of the ictal (seizure) focus by means of recording electrodes inserted into the exposed temporal lobe, a tissue block including the focus may be removed, with abolition of seizures in four out of five cases. Histological examination of the surgical biopsy typically reveals hippocampal sclerosis: the picture is one of glial scarring, with extensive neuronal loss in CA2 and CA3 sectors. The granule cells of the dentate gyrus are relatively well preserved. Loss of inhibitory, GABA internuncials has been blamed in the past but these cells have recently been shown to persist. Instead, the granule cells appear to be disinhibited, because of loss of minute, inhibitory basket cells from among their dendrites.

Because 30% of sufferers from temporal lobe epilepsy have first-degree relatives similarly afflicted, often from childhood, a genetic influence must be significant. One possibility could be ‘faulty wiring’ of the hippocampus during mid-fetal life. Histological preparations show areas of congenital misplacement of hippocampal pyramidal cells, some lying on their sides or even in the subjacent white matter.

The sclerosis is regarded as a typical CNS healing process following extensive loss of neurons. The neuronal loss in turn seems to be inflicted by glutamate toxicity – a known effect of excessively high rates of discharge of pyramidal cells in any part of the cerebral cortex. Dentate granule cells are the main source of burst-firing, which is no surprise in view of their natural role in long-term potentiation and kindling (see main text).

References

Emerson RG, Pedley TA. EEG and evoked potentials. In: Bradley WG, Daroff RB, Finichel GM, Jankovic J, editors. Neurology in clinical practice: principles of diagnosis and management. Philadelphia: Elsevier; 2004:465-490.

Bernasconi N, Bernasconi A, Caramanos Z, et al. Mesial temporal damage in temporal lobe epilepsy: a volumetric MRI study of the hippocampus, amygdala and parahippocampal region. Brain. 2003;126:462-469.

Jay V, Becker LE. Surgical pathology of epilepsy. Pediatr Pathol. 2003;14:731-750.

Kempermann G. The neurogenic reserve rehypothesis: what is adult hippocampal neurogenesis good for? Trends Neurosci. 2008;89:1169-1176.

Niedergerger E, Kuhlein H, Geissler G. Update on the neuropathology of neuropathic pain. Expert Rev proteomics. 2008;5:719-818.

Shin C. Mechanism of epilepsy. Ann Rev Med. 1994;45:379-389.

Willis WD, Westland KR. Pain system. In: Paxinos G, Mai JK, editors. The human nervous system. ed 2. Amsterdam: Elsevier; 2004:1125-1170.

Figure CP 34.3.1 Complex focal seizure. The ictal focus (arrow) occupies the middle–posterior junctional zone of the right temporal lobe (cf. electrode positions in Figure 30.2). Within a second the entire cortex exhibits a secondarily generalized seizure (to the right of the dashed line).

LTP is described as an associative phenomenon, because the required expulsion of the magnesium plug from the NMDA receptor (Figure 34.8) is facilitated when the powerful depolarizing stimulus is coupled with a weaker stimulus to the depolarized neuron from another source. Norepinephrine and dopamine are suitable associative candidates, one or both being released during elevation of the attentional or motivational state at the appropriate time.

Figure 34.8 Long-term potentiation.

Cholinergic activity in the hippocampus is also significant for learning. In human volunteers, central ACh blockade (by administration of scopolamine) severely impairs memory for lists of names or numbers, whereas a cholinesterase inhibitor (physostigmine) gives above-normal results. Clinically, hippocampal cholinergic activity is severely reduced in Alzheimer’s disease (AD), which is particularly associated with amnesia (see Clinical Panel 34.4).

Kindling (‘lighting a fire’) is a property unique to the hippocampal formation and amygdala, although its relationship to learning is not obvious. Kindling is the progressively increasing group response of neurons to a repetitive stimulus of uniform strength. In both humans and experimental animals, it can spread from mesocortex to neocortex and cause generalized convulsive seizures.

The contribution of the fornix projection to memory is uncertain. Indirect evidence has been adduced from diencephalic amnesia, a state of anterograde amnesia which may follow bilateral damage to the diencephalon. Such damage may interrupt the Papez circuit linking the fornix to the cingulate gyrus by way of the mammillary body and the anterior nucleus of the thalamus. Particularly impaired is relational memory (e.g. recollection of the sight and sound of a particular waterfall with the wind blowing spray over some fleeing viewers; recollection of the structure and the function of the (say) left vestibular labyrinth, along with inevitable symptoms and signs that follow sudden occlusion of the left labyrinthine artery.)

Left vs right hippocampal functions

In keeping with known hemispheric asymmetries, the left anterior hippocampus and dorsolateral prefrontal cortex (DLPFC) are engaged in encoding novel material involving language function. Also consistent is the finding that the right hippocampus and right inferior parietal lobe are engaged in spatial tasks such as driving a car (Figure 34.9). Blood flow in the DLPFC increases more on the left side during driving, presumably because of the ‘inner speech’ that occurs when exploring novel territory.

Figure 34.9 Navigation in a virtual environment. (A) Scene from a virtual town. Subjects navigated through the town using a keypad to stay clear of obstacles. PET scans taken during the virtual journey showed increased activation, (B) and (C), within the right hippocampus and (D) and (E) within the right supramarginal gyrus. Orientation (L, R) of the MRIs is for a more general readership.

(Kindly provided by Dr Eleanor Maguire, Wellcome Department of Cognitive Neurology, Institute of Neurology, University College, London, UK, and with permission from the Editor of Current Opinion in Neurobiology.)

Anterior vs posterior hippocampal functions

The hippocampus is about 8 cm in length, and there is evidence for anteroposterior functional specialization with respect to novelty vs familiarity, e.g. when novel material is being read on a screen the left anterior hippocampus is especially active, but with development of familiarity with repeated exposure, activity shifts to the posterior part, suggesting that this region is involved in encoding material into long-term memory.

Long-term medial temporal lobe dependency

Autobiographical recollections typically are mainly visual, whereby we revisit scenes from the past, sometimes from childhood. Clinical studies indicate that medial temporal lobe damage impairs or even deletes such ego-centered (personal) memories whereas allocentered (impersonal), map-like recall of past scenes is preserved. On the other hand, damage to the visual association cortex has the opposite effect.

Prefrontal cortex and working memory

Volunteers have been examined under fMRI while preparing to give a motor response to one or more sensory cues. The mid-region of the prefrontal cortex (area 46) tends to be especially active. It is in a position to tap into memory stores in relevant sensory association areas and to organize motor responses including speech.

Insula

The anterior insula is a cortical center for pain (Box 34.1). The central region is continuous with the frontoparietal and temporal opercular cortex, and it seems to have a language rather than a limbic function. During language tasks, PET scans show activity there as well as in the opercular speech receptive and motor areas – but not in people with congenital dyslexia, where it remains silent (Ch. 32). The posterior insula is interconnected with the entorhinal cortex and the amygdala, and is therefore presumed to participate in emotional responses – perhaps in the context of pain evaluation.

Box 34.1 Pain and the brain

The International Association for the Study of Pain has given the following definition: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

This definition emphasizes the affective (emotional) component of pain. Its other component is sensory-discriminative (‘Where and how much?’).

Table Box 34.1.1 is a glossary of conventional terms used in relation to pain.

Peripheral pain pathways

As already noted in Chapter 9, pain is served by finely myelinated (Aδ) and unmylinated (C) fibers belonging to unipolar spinal ganglion cells. These fibers are loosely known as ‘pain fibers’, although others of similar diameters are purely mechanoreceptors and others again elicit pain only when discharging at high frequency, notably mechanical nociceptors and thermoreceptors. The latter are referred to as polymodal nociceptors in the general context of pain.

From somatic tissues including skin, parietal pleura and parietal peritoneum, muscle, joint capsules, and bone, the distal processes of the ganglion cells travel in all of the spinal nerves. The proximal processes branch within the dorsal root entry zone and span five or more segments of the spinal cord within the posterolateral tract of Lissauer before terminating in laminae I, II and IV of the posterior gray horn. The corresponding fibers of the trigeminal nerve terminate in the spinal nucleus of that nerve.

From the viscera, the distal processes share perineural sheaths with postganglionic fibers of the sympathetic system. The proximal processes mingle with the somatic fibers within Lissauer’s tract and terminate in the same region. As noted in Chapter 13, overlap of somatic and visceral afferent terminals on the dendrites of central pain-projecting neurons is thought to account for referred pain in visceral disorders such as myocardial infarction and acute appendicitis.

Sensitization of nociceptors

Injured tissue liberates molecules including bradykinin, prostaglandin, and leukotrienes, which lower the activation threshold of nociceptors. Injured C fibers also initiate axon reflexes (Ch. 11), whereby substance P ± CGRP (calcitonin gene-related peptide) is liberated into the adjacent tissue, causing histamine release from mast cells. Histamine receptors may develop on the nerve terminals and (as already noted in Ch. 8) produce arachidonic acid by hydrolysis of membrane phospholipids. The enzyme cyclooxidase converts arachidonic acid into a prostaglandin. (The main action of aspirin and other non-steroidal anti-inflammatory analgesics is to inactivate that enzyme, thereby reducing synthesis of prostaglandins.)

The net result is sustained activation of large numbers of C-fiber neurons and sensitization of mechanical nociceptors, manifested by allodynia, where even gentle stroking of the area may elicit pain; and by hyperalgesia, where moderately noxious stimuli are perceived as very painful.

As already noted in Chapter 13, irritable bowel syndrome is characterized by sensitization of nociceptive interoceptors in the bowel wall. That event also underlies the painful urinary bladder condition known as interstitial cystitis.

Sensitization of C-fiber neurons may include gene transcription (Ch. 8), whereby abnormal sodium channels are inserted into the cell membrane of the parent neurons in the posterior root ganglion. Spontaneous trains of impulses generated here are thought to account for occasional failure of quite high-level nerve blocks to abolish the pain.

Neuropathic pain

When a peripheral nerve is severed, and the proximal and distal stumps separated by developing scar tissue, trapped regenerating axons form thread-like balls, called neuromas, that are exqisitely sensitive to pressure. Repetitive activation may prolong the victim’s sufferering by engendering a central pain state (see below). Postherpetic neuralgia is a neuropathic pain that may be a sequel to herpes zoster (‘creeping girdle’), manifested by clusters of watery blisters, usually along the cutaneous territory of an intercostal nerve. The virus concerned may perpetuate the pain by precipitating the gene transcription mentioned above.

Central pain pathways

Central pain-projecting neurons are of two kinds, as described in Chapter 15: nociceptive-specific, with small peripheral sensory fields (about 1 cm²), and wide dynamic range, with fields of 2 cm² or more; these are mechanical nociceptors encoding tactile stimuli by low-frequency impulses and noxious stimuli by high-frequency impulses.

The current consensus is that there exists a lateral, sensory-discriminative pathway and a medial, affective pathway in relation to pain (Figures Box 34.1.1 and 34.1.2).

Lateral pain pathway

For the trunk and limbs, the lateral pathway arises in the posterior gray horn of the spinal cord and projects as the lateral spinothalamic tract to the posterior part of the contralateral ventral posterior lateral nucleus of thalamus. For the head and neck, it commences in the spinal nucleus of the trigeminal nerve and occupies the trigeminothalamic projection to the contralateral posterior medial thalamic nucleus. The onward projection is mainly to the primary somatic sensory cortex (SI), partly to the upper bank of the lateral sulcus (SII). The arrangement is somatotopic, as can be seen on PET scanning when a noxious heat stimulus is applied to different parts of the body. Animal investigations demonstrate intensity responsive, nociceptive-specific neurons in SI, having appropriately small peripheral receptive fields, ideal candidates for encoding the ‘Where and how much?’ aspects of pain.

Onward projections to the posterior parietal cortex and SII are indicated in Figures Box 34.1.1 and 34.1.2.

Not surprisingly, the spinothalamic early warning system stimulates orientation of head and eyes toward the source of pain. As mentioned in Chapter 15, the spinotectal tract ascends alongside the spinothalamic and terminates in the superior colliculus. Its imprint is somatotopic and it elicits a spinovisual reflex to orient the eyes/head/trunk toward the area stimulated. In addition to activation of this phylogenetically ancient (reptilian) reflex, the ‘Where?’ visual channel (Ch. 29) is engaged by association fibers passing to the posterior parietal cortex from SI.

Nociceptive neurons in SII are less numerous, and many also receive visual inputs. They are linked to the insula, which also receives direct inputs from the thalamus. Insular stimulation may elicit autonomic responses such as a rapid pulse rate, vasoconstriction, and sweating. Surprisingly, pre-existing lesions of the insula may abolish the aversive quality of painful stimuli while preserving the location and intensity aspects. The condition is known as asymbolia for pain.

Medial pain pathway

The medial pathway is polysynaptic, via spinoreticular and trigeminoreticular tracts to the contralateral medial dorsal thalamic nucleus (among others), with onward projection to the anterior cingulate cortex. That this area is concerned with the affective component of pain experience is strongly supported by the effect of surgical undercutting (cingulotomy) or removal (cingulectomy) as a treatment for chronic pain. Patients report that the intensity of their pain is unchanged but that it has lost its aggressive nature. Precisely the same result follows morphine injection – presumably because the anterior cingulate has the greatest number of opiate receptors in the cerebral cortex.

Following cingulotomy, edema of the bladder control area frequently causes temporary urinary incontinence. More importantly, more than half of all patients show permanent ‘flatness of affect’, i.e. low experience of either elation or depression.

An unexpected stab of pain from any source is likely to generate an immediate sense of fear. This is attributable to activation of spinomesencephalic fibers projecting to the midbrain reticular formation, with onward projection to the amygdala, a nucleus particularly associated with the sense of fear (see main text). Some of the fibers are believed to ascend in or alongside the posterolateral tract of Lissauer; they may account for the persistence of pain perception in some patients following the cordotomy procedure.

Central pain states

Central pain states are almost always generated by wind-up of the CPPNs of the spinothalamic and spinoreticular pathways. One or more of three mechanisms may be responsible:

• Repetitive activation of NMDA glutamate receptors by posterior nerve root inputs, over a period of weeks or months, tends to induce a state of long-term potentiation of CPPNs.

• The threshold of CPPNs may be lowered further by gene transcription whereby additional glutamate receptors are inserted into their dendrites.

• The term ‘paradoxical’ seems appropriate for the third mechanism. Reference was made in Chapter 24 to supraspinal antinociception, whereby serotonergic neurons projecting from the medullary magnus raphe nucleus (MRN) to the posterior gray horn may inhibit CPPNs by activating internuncial enkephalinergic neurons. Evidence from animal experiments now indicates that while either of the first two mechanisms may initiate a central pain state, its maintenance requires that non-serotonergic neurons in or near MRN facilitate CPPNs by a direct excitatory transmitter of uncertain nature. Following limb amputation, an ultimate expression of wind-up is phantom limb pain, where, following limb amputation, severe pain may be experienced in the distal part of the missing limb.

As mentioned in Chapter 27, the central pain state known as thalamic syndrome may develop following a vascular lesion in the white matter close to the ventroposterior nucleus of the thalamus. Explanation of the bouts of severe contralateral pain sensation may lie in elimination of the normal inhibitory feedback to the posterior thalamus from the surrounding thalamic reticular nucleus.

References

Benarroch EE. Descending monoaminergic pain modulation. Neurology. 2008;71:217-221.

Brooks J, Tracey I. From nociception to pain perception: imaging the spinal and supraspinal pathways. J Anat. 2005;207:19-33.

Froth M, Mauguiere M. Dual representation of pain in the operculo-insular cortex in humans. Brain. 2003;126:438-450.

Gatchel RJ. Clinical essentials of pain management. Washington: American Association; 2005.

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Villanueva L, Nathan PW. Multiple pain pathways. In: Progress in pain research and management. Seattle: IASP Press; 2000:371-386.

Willis WD, Westlund KR. Pain system. In: Paxinos G, Mai JK, editors. The human nervous system,. ed 2. Amsterdam: Elsevier; 2004:1125-1170.

Table Box 34.1.1

Term	Meaning
Allodynia	Pain produced by normally innocuous stimuli. Examples: stroking sunburned skin; moving an inflamed joint.
Central pain-projecting neurons (CPPNs)	An inclusive conventional term denoting all posterior horn neurons projecting pain-encoded information to contralateral brainstem and thalamic nuclei. Pathways included are: spinothalamic, the lateral pain pathway to posterior nucleus of thalamus; spinoreticulothalamic, medial pain pathway to the medial and intralaminar nuclei of thalamus via brainstem reticular formation; spinoamygdaloid, to the amygdala via the reticular formation; and spinotectal, to the superior colliculus.
Central pain state	A state of chronic pain, resistant to therapy, sustained by hypersensivity of peripheral and/or central neural pathways.
Wind-up phenomenon	Sustained state of excitation of CPPNs induced by glutamate activation of NMDA receptors.
Fast pain	Stabbing pain perceived following activation of Aδ nociceptors.
Hyperalgesia	Hypersensitivity to stimulation of injured tissue, and of surrounding uninjured tissue. Causes include mechanical or thermal damage, bacterial/viral inflammation, small-fiber peripheral axonal neuropathy, radiculopathy (posterior nerve root injury).
Neurogenic inflammation	Inflammation caused by liberation of substance P (in particular) following antidromic depolarization of fine peripheral nerve fibers.
Neuropathic pain	Chronic stabbing or burning pain resulting from injury to peripheral nerves. Examples: postherpetic neuralgia; amputation neuroma.
Nociceptors	Peripheral receptors whose activation generates a sense of pain. These receptors occupy the plasma membrane of fine nerve endings and contain transduction channels that convert the requisite physical or chemical stimulus into trains of impulses decoded by the brain as a sense of pain.
Polymodal nociceptors	Peripheral nociceptors (notably in skin) responsive to noxious thermal, mechanical, or chemical stimulation.
Sensitization	Lowering the threshold of peripheral nociceptors by histamine (in particular) following peripheral release of peptides via the axon reflex.
Slow pain	Aching pain perceived following activation of C-fiber nociceptors.

Figure Box 34.1.1 Areas showing increased metabolic activity following application of noxious heat to the right forearm.

Figure Box 34.1.2 Pain pathways. Note: Violet signifies having emotional signifiance.

The amygdala is in fact anterior to the plane of section in the diagram and areas 5 and 7 are posterior to it.

1 Peripheral nociceptive neurons project to posterior gray horn.

2 ‘Fast’ CPPNs project direct to contralateral posterolateral thalamus and

3 relay to somatic sensory cortex (SI).

4 Association fibers connect SI to posterior parietal cortex both for ‘Where’ and ‘How much’ tactile analysis, and to provide a ‘Where?’ visual alert.

5 Posterior parietal cortex projects to SII for tactile-visual integration. Onward relay to the insular cortex, supplemented by some direct thalamic inputs there, may elicit autonomic and emotional responses.

6 ’Slow’ CPPNs relay via the reticular formation to the medial thalamus, with forward projection to the prefrontal cortex (not shown here) for overall evaluation.

7 Upward projection to the cingulate cortex normally generates an aversive (L. ‘turn away’) emotional evaluation.

8 Some CPPNs excite reticular neurons projecting to the amygdala, where they are likely to generate a sense of fear.

Cingulate cortex and posterior parahippocampal gyrus

The cingulate cortex is part of the Papez circuit, receiving a projection from the anterior nucleus of the thalamus and becoming continuous with the parahippocampal gyrus behind the splenium of the corpus callosum.

The anterior cingulate cortex belongs to the rostral limbic system, which includes the amygdala, ventral striatum, orbitofrontal cortex, and anterior insular cortex.

Six functional areas can be discerned in the anterior cingulate cortex (Figure 34.10).

1 An executive area is connected directly with the DLPFC and with the supplementary motor area (SMA). The executive area becomes active prior to execution of willed movements, including voluntary saccades (Ch. 29) – and even prior to the SMA itself. The executive area is thought to have special significance, together with the DLPFC, in generating appropriate motor plan selection by the SMA.

2 A pain perception area receives afferents from the medial dorsal nucleus of the thalamus (Box 34.1).

3 An emotional area lies close to the pain perception area. When volunteers ‘think happy’ while undergoing PET scans, the anterior cingulate cortex ‘lights up’ and the amygdala ‘switches off’. A reverse result occurs when volunteers ‘think sad’. Anterior cingulectomy has often been performed in the past, yielding successful control of aggressive psychiatric disorders.

4 A bladder control area becomes increasingly active during bladder filling (Ch. 24).

5 A vocalization area becomes active, together with the DLPFC, during decision-making about appropriate sentence construction for speech activity. Electrical stimulation of this area causes jumbling of speech. Stammering in children is associated with reduced blood flow in the left anterior cingulate gyrus during speech. Blood flow there is also reduced in people suffering from Tourette’s syndrome, which is characterized by brief, loud utterances of a single syllable or phrase, often offensive to the ear.

6 An autonomic area, below the rostrum of the corpus callosum, elicits autonomic and respiratory responses when stimulated electrically. This area is thought to participate in eliciting the visceral responses typical of emotional states.

Figure 34.10 Functional areas in the anterior cingulate cortex. SMA, supplementary motor area.

The posterior cingulate gyrus (area 23 of Brodmann) merges with the posterior parahippocampal gyrus (area 36). This cortical complex is richly interconnected with visual, auditory, and tactile/spatial association areas. The complex evidently contains memory stores related to these functions because PET studies reveal increased activity there when scenes or experiences are conjured up in the mind. The complex is also engaged during reading (Ch. 32).

Amygdala

The amygdala (Gr. ‘almond’; also called the amygdaloid body or amygdaloid complex) is a large group of nuclei above and in front of the temporal horn of the lateral ventricle and anterior to the tail of the caudate nucleus. The amygdala is primarily associated with the emotion of fear, as illustrated by the effect of looking at an angry or fearful face (Figure 34.11). Current clinical and basic science ambition is to gain diagnostic and therapeutic insights into the role of the amygdala with regard to various phobias and anxiety states prevalent in both the young and the adult population. The connections of the amygdala (inasmuch as these are understood) are consistent with the present perception of a ‘bottleneck’ position in the perception and expression of fear.

Figure 34.11 Cross-modal emotional responses. (A) Coronal structural MRI image showing a superimposed fMRI map of bilateral activation of the amygdala in a volunteer observing a fearful face accompanied by a fearful voice (see C). At the opposite end of the spectrum, amygdalar activity was below normal level in the presence of a happy face and voice. (B) The associated graph shows experimental condition-specific fMRI responses in the amygdala.

(Kindly provided by Professor R.J. Dolan, Wellcome Department of Cognitive Neurology, Institute of Neurology, University College, London, UK.)

Afferent pathways

Within the amygdala, nuclear groups receiving afferents are predominantly laterally placed and are usually referred to collectively as the lateral nucleus. In Table 34.1 and related Figures, the afferents are segregated into subcortical and cortical.

Table 34.1 Afferents to lateral nucleus of amygdala

Nature	Subcortical source	Cortical source
Tactile	Ventral posterior nucleus of thalamus	Parietal lobe
Auditory	Medial geniculate body	Superior temporal gyrus
Visual	Lateral geniculate body*	Occipital cortex
Olfactory	—	Piriform lobe
Mnemonic	—	Hippocampus/entorhinal cortex
Cardiac	Hypothalamus	Insula
Nociceptive	Midbrain reticular formation	—
Cognitive	—	Orbital cortex
Attention-related	Cerulean nucleus	Basal nucleus of Meynert

* Afferents from LGB to amygdala have yet to be clearly identified.

Subcortical access, depicted in Figure 34.12, is thought to be especially important in infancy and childhood, at a time when the amygdala is developing faster than the hippocampus and is capable of acquiring fearful memory traces without hippocampal participation. Such memories cannot be consciously recalled at any later time despite generating physical responses of an ‘escape’ nature. The general-sense and special-sense pathways listed and depicted are sufficiently comprehensive to account for the acquisition of almost any specific ‘unexplained’ phobia (e.g. enclosed spaces, smoke, heights, dogs, faces).

Figure 34.12 Subcortical afferents to lateral nucleus of amygdala. IC, inferior colliculus; LGB, MGB, lateral, medial geniculate body; VPN, ventral posterior nucleus of thalamus.

As indicated in Figure 34.13, all sensory association areas of the cortex have direct access to the lateral nucleus of the amygdala. These areas are also linked to the prefrontal cortex through long association fiber bundles, rendering all conscious sensations subject to cognitive evaluation.

Figure 34.13 Cortical afferents to lateral nucleus of amygdala. V4, object/face recognition area; V5, motion detection area.

Activity of the visual association cortex is especially important in connection with phobias and anxiety states. Area V4 at the inferior surface of anterior area 19 is a link in the object/face recognition pathway. V5, at the lateral surface of anterior area 19, is a link in the movement detection pathway. Both are connected to the amygdala via the hippocampus, where fearful visual memories may be recalled by the current visual scene. The visual association cortex is also important in that fearful visual images conjured in the mind independently of current sensation may activate the amygdala. This capability has resonance in relation to post-traumatic stress disorder, where a seemingly innocent scene may cause the afflicted individual to ‘relive’ a horrific visual experience, up to 20 years or more after the event. In the multimodal anterior region of the superior temporal gyrus, where sound and vision coalesce, a door banged shut may induce a ‘virtual reality’ re-enactment of a horrific encounter, e.g. of a haunting war experience.

The orbital prefrontal cortex of the right side, with its bias toward ‘withdrawal’ rather than ‘approach’ (Ch. 32), is commonly active (in PET scans) along with the right amygdala in fearful situations, e.g. when a specific phobia is presented to a susceptible subject. On the one hand, this offers the ‘downside’ potential to ‘feed on one’s fear’. On the other hand, expert social/psychological conditioning may eventually suffice to reduce the ‘negative drive’ of the orbital cortex. When conditioning is combined with use of anxiolytic drugs, specific phobias may be abolished completely.

The insula is omitted from Figure 34.13 but, as noted earlier, its posterior part also has direct access to the amygdala, probably related to the emotional evaluation of pain.

Finally, the basal nucleus of Meynert is listed. The cholinergic projection from this nucleus is thought to be of significance in facilitating cortical cell columns in the context of situations having negative emotional valence. Meynert activity appears to be heightened in association with anxiety, generating a raised level of autonomic activity involving the amygdala (and/or the adjacent bed nucleus of the stria terminalis, mentioned below).

Efferent pathways (Table 34.2)

Easily identified in the postmortem brain is the stria terminalis (Figure 34.14), which, upon emerging from the central nucleus of the amygdala, follows the curve of the caudate nucleus and accompanies the thalamostriate vein along the sulcus terminalis between thalamus and caudate nucleus. The stria sends fibers to the septal area and hypothalamus before entering the medial forebrain bundle and (downstream) the central tegmental tract. Some fibers of the stria terminate in a bed nucleus, above the anterior commissure. The bed nucleus is regarded by some workers as part of the ‘extended amygdala’; it may be more active than the amygdala proper, on PET scans, in anxiety states.

Table 34.2 Efferents from central nucleus of amygdala

Target nucleus/pathway	Function/effect
Periaqueductal gray matter (to medulla/raphespinal tract)	Antinociception
Periaqueductal gray matter (to medullary reticulospinal tract)	Freezing
Cerulean nucleus	Arousal
Norepinephrine medullary neurons (projection to lateral gray horn)	Tachycardia/hypertension
Hypothalamus/dorsal nucleus of vagus (to heart)	Bradycardia/fainting
Hypothalamus (liberation of corticotropin-releasing hormone)	Stress hormone secretion
Parabrachial nucleus (to medullary respiratory nuclei)	Hyperventilation

Figure 34.14 Efferents from central nucleus of amygdala via stria terminalis. The only postsynaptic pathways shown are autonomic. The periaqueductal gray matter (PAG) projects to magnus raphe neurons (MRN), giving rise to the raphespinal tract. ACTH, adrenocorticotropic hormone; BNST, bed nucleus of stria terminalis. CN, nucleus ceruleus; MRN, magnus raphe nucleus; PBN, parabrachial nucleus; RF, reticular formation; X, dorsal nucleus of vagus.

A second efferent projection, the ventral amygdalofugal pathway, passes medially to synapse within the nucleus accumbens (Figure 34.15). This connection is considered in the context of schizophrenia (Clinical Panel 34.4).

Figure 34.15 Coronal section at the level of the nucleus accumbens highlighting distribution of dopaminergic fibers arising in the ventral tegmental nuclei (VTN) of the midbrain.

Clinical Panel 34.4 Alzheimer’s disease (AD)

Dementia is defined as a severe loss of cognitive function without impairment of consciousness. AD is the commonest cause of dementia, afflicting 5% of people in their seventh decade and 20% of people in their ninth. AD patients fill 20% of all beds in psychiatric institutions.

MRI brain scans usually reveal severe atrophy of the cerebral cortex, with widening of the sulci and enlargement of the ventricular system. As seen in Figure CP 34.4.1, the medial temporal lobe (hippocampal complex and entorhinal cortex) are most severely affected. The primary sensory and motor areas, and the upper regions of the prefrontal cortex, are relatively well preserved.

Postmortem histological studies of the cerebral cortex reveal:

• Extensive loss of pyramidal neurons throughout the brain.

• Amyloid plaques and neurofibrillary tangles, notably in the hippocampus and amygdala. The plaques begin in the walls of small blood vessels and have been explained in terms of an enzyme defect resulting in abnormal, beta-amyloid protein production. The tangles are made up of clumps of microtubules associated with an abnormal variant of a microtubule-associated tau protein. The tangles are progressively replaced by amyloid.

• Loss of up to 50% of the cholinergic neurons from the basal nucleus of Meynert and from the septal area, together with their extensive projections through the cerebral isocortex and mesocortex. Indeed, degenerating ACh terminals seem to contribute to the neurofibrillary tangles in the temporal lobe.

Hypometabolism can be shown on PET scans arranged to detect glucose utilization. This is attributable in part to loss of pyramidal cells, and in part to loss of cholinergic innervation of the pyramidal cells remaining. Healthy pyramidal neurons have excitatory ACh receptors in their cell membranes.

Although the pattern of degeneration varies from case to case, its general trend is to commence in the medial temporal lobe and to travel upward and forward. The following clinical features are explained in that sequence:

• Dwindling hippocampal function. Anterograde amnesia leads to forgetfulness, e.g. recounting a personal event within minutes of telling it (loss of present-time episodic memory); difficulty in finding one’s way around familiar streets, or alarming misjudgments while driving an automobile (hippocampal activity is required to sustain parietal lobe spatial sense); attentional deficit, whose earliest manifestation is an inability to switch attention from one thing to another.

• Dwindling occipitotemporal function. Damage to area 37 leads to an inability to read and write. Damage to the temporal polar region leads to distressing failure to recognize the faces of family and friends. Involvement of the supramarginal and angular gyri leads to an inability to write.

• Dwindling frontal lobe function. Usually within 3 years of onset, the patient is ‘spaced out’, staring at walls and seemingly unaware of what is going on in the room. This ‘vacant’ state lasts for up to 5 or 6 years antemortem.

An unusual variant, known as early-onset AD, shows clear evidence of an autosomal dominant trait. The illness appears during the fourth or fifth decade. Chromosomal analyses have revealed a specific mutation in the gene coding for amyloid precursor protein on the long arm of chromosome 21. This mutation is also found in Down’s syndrome, where sufferers surviving into middle age usually develop AD.

References

Duara R, Loewenstein DA, Potter E, et al. Medial lobe temporal atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology. 2008;71:1986-1992.

Gendron TF, Petrucelli L. The role of tau in neurodegeration. Mol Neurodegener. 2009;4:13-51.

Whitwell JL, Jack CR Jr. Neuroimaging in dementia. Neurol Clin. 2007;25:843-857.

Figure CP 34.4.1 Coronal MRI slices. (A) Normal control. (B) Alzheimer’s patient. (Images supplied by Professor Clifford R. Jack, Jr., and the Alzheimer’s Disease Research Center at the Mayo Clinic.)

Colors added: green = hippocampus; red = entorhinal cortex.

Notes on the efferent target connections

Periaqueductal gray matter (PAG). A source of supraspinal antinociception was described in Chapter 24, namely the opioid-containing axons from the hypothalamus which disinhibit the excitatory projection from the PAG to the serotonergic cells of origin of the raphespinal tract. The excitatory cells of the dorsal PAG are directly stimulated by axon terminals entering from the amygdala via the medial forebrain bundle.

In laboratory animals, stimulation of the ventral PAG causes freezing, where a fixed, flexed posture is adopted. The ventral PAG contains neurons projecting to the cells of origin of the medullary reticulospinal tract. This tract activates flexor motor neurons during the walking cycle, and intense activation may cause a frightened person to ‘go weak at the knees’ and perhaps fall down.

Cerulean nucleus. Facilitation of excitatory cortical neurons by the noradrenergic projection from this pontine nucleus is to be expected.

Medullary adrenergic neurons. As noted in Chapter 24, these neurons are a component of the baroreflex pathway sustaining the blood pressure against gravitational force. Sudden stimulation by the direct projection from the amygdala may send the heart dullthudding and cause a major elevation of systemic blood pressure.

Hypothalamus. Fibers of the stria terminalis synapse upon two sets of hypothalamic neurons. The first, located in the anterolateral region, sends axons into the dorsal longitudinal fasciculus to synapse in cells of origin of the vagal supply to the heart. The well-known condition, referred to by psychiatrists as blood trauma phobia (fainting at the sight of blood at the scene of an accident), is characterized by initial sympathetic excitation followed by vagus-induced bradycardia causing the individual to collapse (faint).

The second set of neurons secrete corticotropin-releasing hormone (CRH) into the adenohypophysis via the hypophyseal portal system, with consequent release of adrenocorticotropin (ACTH). Curiously, these CRH neurons send collateral branches into the central nucleus of the amygdala, with positive feedback enhancement of its activity.

Parabrachial nucleus. In individuals subject to panic attacks, hyperventilation, together with a sense of fear, may be triggered by what may appear to be relatively trivial environmental challenges. Normally, the respiratory alkalosis produced by washout of carbon dioxide reduces the respiratory rate causing the blood pH to return to normal, whereas susceptible individuals continue to hyperventilate. Because selective serotonin reuptake inhibitors (SSRIs) are highly successful in treatment, the prevailing view is that the normal inhibitory role of serotonergic terminals within the nucleus accumbens (see below) has become deficient. However, overactivity of the cerulean nucleus has also been implicated because the drug yohimbine can induce a panic attack, apparently through norepinephrine release.

Limbic striatal loop. This circuit is depicted in Chapter 33, passing from the prefrontal cortex through the nucleus accumbens and medial dorsal nucleus of thalamus, with return to the prefrontal cortex. However, the central nucleus of the amygdala participates in this circuit through an excitatory projection to the nucleus accumbens. In the right hemisphere, this projection is likely to facilitate a withdrawal response; in the left, it may facilitate an approach response.

Bilateral ablation of the amygdala has been carried out in humans for treatment of rage attacks, characterized by irritability, building up over several hours or days to a state of dangerous aggressiveness. This controversial operation has been successful in eliminating such attacks. In monkeys, bilateral ablation leads to placidity, together with a tendency to explore objects orally and to exhibit hypersexuality (Klüver–Bucy syndrome). A comparable syndrome has occasionally been observed in humans.

At the other end of the spectrum, PET studies of incarcerated murderers have revealed that the amygdala of the majority remains ‘silent’ even when gruesome scenes are presented on screen.

Nucleus accumbens

The full name is nucleus accumbens septi pellucidi, ‘the nucleus leaning against the septum pellucidum’. More accurately, the nucleus abuts septal nuclei located in the base of the septum. Figures 34.15 and 34.18C show this relationship. The accumbens is one of many deep-seated brain areas where electrodes have been inserted on a therapeutic trial basis, notably in the hope of providing pain relief. Stimulation of the accumbens induces an intense sense of well-being (hedonia), comparable to that experienced by intake of drugs of addiction such as heroin (see Clinical Panel 34.5). This ‘high’ feeling is attributed to flooding of the nucleus, and of the medial prefrontal cortex, by synaptic and volume release of dopamine from the neurons projecting from the ventral tegmental area. Normally, dopamine is released in small amounts and quickly retrieved from the extracellular space by a specific dopamine reuptake transporter.

Clinical Panel 34.5 Drugs of dependency

Experimental evidence from the injection of drugs of abuse has yielded the following results (Figures CP 34.5.1 and 34.5.2):

• Cocaine binds with the dopamine reuptake transporter, blocking reuptake of the normal secretion with consequent dopamine accumulation in the extracellular space.

• Amphetamine and methamphetamine are potent dopamine-releasing agents and also tend to block the reincorporation of dopamine into synaptic vesicles. These two drugs are also significantly active within the terminal dopaminergic network in the prefrontal cortex.

• Cannabinoids activate specific, excitatory, cannabinoid receptors on dopamine nerve endings.

• Nicotine attaches to specific excitatory receptors in the plasma membrane of parent somas in the midbrain.

• Opioids such as morphine and dihydromorphine (heroin) activate specific inhibitory receptors located in the plasma membrane of GABAergic internuncial neurons within the nucleus. These neurons normally exert a tonic braking action on the projection cells of the ventral tegmental nuclei. Opioid-induced hyperpolarization of the internuncials leads to functional disinhibition of the projection cells, with consequent increased activity of both mesolimbic and mesocortical neurons.

• Ethanol also interferes with normal GABAergic activity. It binds to postsynaptic GABA membrane receptors throughout the brain without activating them; again, the target neurons become more excitable.

Serotonergic and noradrenergic neurons projecting to limbic system and hypothalamus have also been implicated in connection with drug dependency, notably in expressing some of the effects of abrupt drug withdrawal.

Reference

Heimer L, Van Hoesen GW, Trimble M, Zalm S. Anatomy of the basal forebrain. In: The anatomy of psychiatry. Amsterdam: Elsevier; 2008:27-67.

Staley JK, Mash DC. Adaptive increase in D₃ dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci. 1996;16:610-616.

Figure CP 34.5.1 Mesolimbic neuron supplying nucleus accumbens, showing sites of action of some drugs of dependency.

Figure CP 34.5.2 Intense activation (red) of D₃ receptors (D₂ variants) in the nucleus accumbens of a cocaine addict.

(From Staley and Mash, 1996, with permission.)

Septal area

The septal area comprises the septal nuclei, merging with the cortex directly in front of the anterior commissure, together with a small extension into the septum pellucidum (Figure 34.16).

Figure 34.16 Connections of the septal area. MDN, mediodorsal nucleus of thalamus.

Afferents to the septal nuclei are received from:

• the amygdala, via the diagonal band (of Broca), a slender connection passing alongside the anterior perforated substance;

• the olfactory tract, via the medial olfactory stria;

• the hippocampus, via the fornix; and

• brainstem monoaminergic neurons, via the medial forebrain bundle.

The two chief efferent projections are the:

• stria medullaris, a glutamatergic strand running along the junction of side wall and roof of the third ventricle to synapse upon cholinergic neurons in the habenular nucleus. The habenular nuclei of the two sides are connected through the habenular commissure located close to the root of the pineal gland, as shown earlier, in Figure 17.20. The habenular nucleus sends the cholinergic habenulo-interpeduncular tract (fasciculus retroflexus) to synapse in the interpeduncular nucleus of the reticular formation in the midbrain (Figure 17.19). The interpeduncular nucleus is believed to participate in the sleep–wake cycle together with the cholinergic neurons beside the cerulean nucleus, identified earlier (Figure 24.3).

• septohippocampal pathway, running to the hippocampus by way of the fornix (Figure 34.17). It is responsible for generating the slow-wave hippocampal theta rhythm detectable in EEG recordings from the temporal lobe. Glutamatergic neurons in this pathway are pacemakers determining the rate of theta rhythm; cholinergic neurons determine the size of the theta waves. Theta rhythm is produced by synchronous discharge of groups of hippocampal pyramidal cells, and is significant in the development of biochemical alterations within pyramidal glutamate receptors during the long-term potentiation involved in laying down episodic memory traces. The strength of theta rhythm is greatly reduced in AD, reflecting the substantial loss of both cholinergic neurons and episodic memory formation and retrieval in this disease.

Figure 34.17 Septohippocampal pathway (1) with return projection from hippocampus (2).

Electrical stimulation of the human septal area produces sexual sensations akin to orgasm. In animals, an electrolytic lesion may evince signs of extreme displeasure (so-called ‘septal rage’). This surprising response may be due to destruction of a possible inhibitory projection from septal area to amygdala.

Basal forebrain

The basal forebrain extends from the bifurcation of the olfactory tract as far back as the infundibulum, and from the midline to the amygdala (Figure 34.18). In the floor of the basal forebrain is the anterior perforated substance, pierced by anteromedial central branches arising from the arterial circle of Willis (Ch. 5). Here the cerebral cortex is replaced by scattered nuclear groups, of which the largest is the magnocellular basal nucleus of Meynert.