The Posterior Perforated Substance: A Brain Mystery Wrapped in an Enigma
IMPORTANCE: There is a dearth of published information on the posterior perforated substance (PPS) as compared to the anterior perforated substance. We managed to glean facts about the PPS that can serve as a landmark for surgical operations in the adjacent regions of the midbrain and the vessels passing through it. Moreover, PPS contains the interpeduncular nucleus responsible for the mental state of the individual.
OBJECTIVES: 1) To describe the anatomy and topography of the blood vessels supplying the PPS area; 2) to review surgical interventions in patients with aneurysm of cerebral arteries; 3) to investigate the interpeduncular nucleus, its vasculature, and its functions;
DESIGN, SETTING: We assembled and analyzed results from source databases by Elsevier, NCBI MedLine, Scopus, Scholar.Google and Embase. Each article was studied in detail for practically useful information about the PPS.
MAIN OUTCOMES: During the surgical treatment of cerebral aneurysms, the PPS area is vulnerable to injuries from disrupting the integrity of the small arterial branches that penetrate the PPS. There is possible collateral damage to the interpeduncular nucleus as well.
RESULTS: The P1-segment perforating branches of the posterior cerebral artery supply the PPS. This area is especially vulnerable in the case of vascular pathologies, such as an aneurysm of the upper basilar artery. The posterior communicating artery can block the surgeon’s view and impede maneuverability of the tool in the area of the PPS, which may be addressed using the separation technique, which can lead to positive results. In addition, the medial habenula-interpeduncular nucleus in the PPS is associated with various addictions, psychiatric conditions, mood swings, and impacts on sleep.
CONCLUSIONS AND RELEVANCE: The PPS area is of great interest for surgical interventions. Future studies of the medial habenula-interpeduncular nucleus way inform the development of drugs to affect different types of dependencies and some mental diseases.
Keywords: posterior perforated substance; interpeduncular fossa; thalamoperforating arteries; posterior communicating arteries; medial habenula; MHb; interpeduncular nucleus; IPN; MHb-IPN axis; MHb-IPN way.
The anatomical structure of the mesencephalic ventral surface, known as the posterior perforated substance (PPS) has a complex topography. That can lead to problems during surgical interventions in the area. The PPS forms the bottom of the third ventricle. It is infiltrated by small branches of the posterior cerebral arteries that carry blood to the thalamus. In addition, the PPS contains the interpeduncular nucleus (IPN). The IPN has a broad inhibitory effects and is connected to inputs via the medial habenula and outputs to the thalamus, various nuclei, and the hypothalamus. Knowledge of the topography, histology, and vascularization enable the surgeon to use the PPS as a landmark during surgical interventions on adjacent areas of the mesencephalon and vessels passing through it.
In open sources, there is a lack of information about the PPS compared to the anterior perforated substance. This study addresses the insufficient knowledge. Therefore, this review will be useful both for medical students and for specialists in the field of neurology and neurosurgery.
The purpose of this article is to provide a detailed review of the PPS using various sources.
Accordingly, the authors sought to:
1) Describe the anatomy and topography of the blood vessels supplying the PPS;
2) Review surgical interventions in patients with aneurysm of the upper part of the basilar artery; and
3) Investigate the IPN as well as its functions.
Materials and methods
The published literature was analyzed relative to the PPS, its arterial supply, surgical operations, as and neural pathways. Sources included databases by Elsevier, NCBI MedLine, Scopus, Scholar. Google, and Embase. We restricted the search to January 1900 through April 2019.
Interpeduncular fossa and the PPS
There is a depression on the ventral side between right and left peduncles of the midbrain. This depression is known as the interpeduncular fossa and Tarin’s fossa (Figure 1A). It is narrow at the upper margin of the pons, expands anteriorly and ends just near two mammillary bodies identified as the diencephalon. Tarin’s fossa is delimited:
- Cranially, by the mammillary bodies (4 to 6 mm in diameter) and the anterior half of the posterior perforated substance;
- Dorsally, by the posterior half of the PPS and the anterior part of the mesencephalic tegmentum;
- Caudally, by the superior area of the pons, which extends beyond the interpeduncular fossa in the anterior direction, and the mesencephalopontine sulcus;
- Laterally, by the prolapsing cerebral peduncles, their salient ventral part anterior to the substantia nigra area called “crus cerebri”; and
- Ventrally, by the bifurcation of the basilar artery and the proximal section of both posterior cerebral arteries.
The surface of the interpeduncular fossa has a tint of gray and is penetrated by numerous blood vessels. This formation of the mesencephalon is called the posterior perforated substance or paramedian perforated substance (Figure 1B). The PPS is a triangular depression that consists of gray matter formed by a cluster of neural cell bodies that forms the bottom of the third ventricle.
The base of this plate is triangular with length of 3.25 ± 0.29 mm. It is located anteriorly, in front of the posterior margin of the mammillary bodies. The top part of the plate is located posteriorly and is formed by the diverging angle of the cerebral peduncles and the mesencephalopontine sulcus. The distance between the top of the plate and its base is 8.11 ± 1.19 mm. All in all, the PPS has 4 parts: anterior, posterior, top, and low.
Blood supply of the PPS area
The arteries supplying the diencephalon penetrate the top part, the arteries supplying the mesencephalon penetrate the low and posterior parts1,2. The posterior communicating artery originates from the posterior-medial surface of the internal carotid artery, passes behind (in the upper-medial direction) the oculomotor nerve, and joins the posterior cerebral artery3. For clarity, the posterior cerebral artery is divided into four segments which are designated as P1, P2, P3 and P43,4,5,6.
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The P1 segment is called the pre-connective segment. It originates from the bifurcation of the basilar artery, bends the oculomotor nerve from above (in relation to the anterior-medial part of the cerebral peduncle), and connects with the posterior communicating artery. The P1 segment is usually the origin of such important branches as the thalamoperforating arteries, the short circumflex arteries, the long circumflex arteries, and sometimes the medial posterior choroidal arteries3. They supply crucial structures: the interpeduncular fossa, posterior perforated substance, cerebral peduncles, the mamillary bodies, tegmentum, thalamus, hypothalamus, internal capsule and the deep nuclei of the basal ganglia, brainstem and quadrigeminal plate7,8,9. Therefore, damage to any of these branches leads to serious consequences.
Perforating branches of the P1 segment are vulnerable to injury during surgery on vascular pathologies such as basilar apex aneurysms. This type of pathology remains the most common of posterior circulation aneurysms and remains difficult to treat with surgical methods. During the surgery it is extremely important to identify and preserve these perforators. Thus, comprehensive knowledge about the microsurgical anatomy of this area is necessary to prevent undesirable postoperative consequences10.
All thalamoperforating arteries originate from the posterior-upper side of the P1 segment. Kaya et al. confirms that in their study thalamopoerforating artery was the most proximal branch among all perforators10. Rhoton concludes that the branches of the P1 segment refer to the thalamoperforating arteries, the short circumflex arteries, the long circumflex arteries, and to the medial posterior choroidal arteries3. Usually they take off from the superior and posterior sides of the P1 segment with an average value of 4 branches per this segment. P1’s diameter can reach 1.5 mm.3 These branches mainly pass through the interpeduncular fossa, the posterior perforated substance, the peduncles of the brain, the mammillary bodies, and the posterior part of the mesencephalon.
The largest branch of the P1 segment is the posterior thalamoperforating artery or the medial posterior choroidal arteries, more rarely, the branch that gives rise to both arteries. In most cases, the posterior thalamoperforating arteries pass into the brain through the posterior perforated substance, the medial part of the brain peduncles, and the upper part of the interpeduncular fossa.
The circumflex branches can originate from the P1 and P2 segments. They split into the short circumflex arteries and the long circumflex arteries3. The short circumflex arteries medially pass to the long circumflex arteries and to the medial posterior choroidal arteries and reach the medial geniculate bodies3. They can supply the cerebral peduncles, the interpeduncular fossa, and the posterior perforated substance. These structures are supplied by thalamoperforating arteries.
The posterior communicating artery gives rise to 2 to 17 perforating branches3,9,11,12,13, which can be divided into tuberoinfundibular, optical, mammillary, and peduncle branches. The posterior communicating artery also gives rise to the pre-mammillary or tuberothalamic artery14.
These perforating branches pass through the posterior perforated substance in the perimamillary or retrooptical region9,15. In 54% of the samples studied by Saeki et al., most of the perforating branches originated from the anterior half of the posterior communicating artery. In 25% of the samples they took off from the posterior half of the posterior communicating artery. In 21% of the samples they equally branched off from both segments12. The quantity and the size of these perforating branches were not correlated with the diameter of the posterior communicating artery13.
The anterior choroidal artery mainly branches off the lower lateral posterior wall of the internal carotid artery, which is about 2-4 mm more distal from the posterior communicating artery. The quantity of the perforating branches taking off between the origin of the anterior choroidal artery and the posterior communicating artery varies from 0 to 4. Perforating branches mainly supply the medial temporal structures (the lateral branches are associated with them), the optic tract (associated with the medial branches) and the posterior perforated substance (associated with the upper branches). In most of the hemispheres studied by Michael George Z. et al, the anterior choroidal artery is the only branch of the internal carotid artery16.
M. Yashar S. Kalani et al “The interpeduncular fossa approach for resection of ventromedial midbrain lesions”, 2017
Figure 1A: The interpeduncular fossa is a wedge-shaped depression between the cerebral peduncles. Its bottom is lined with the posterior perforated substance. The most caudal point of the fossa is the superior foramen cecum (it is a depression located in the middle). The oculomotor nerves (the 3rd pair of cranial nerves) extend from the side walls of the fossa.
Figure 1B: Sagittal section of the brain. The following structures are nearby to the posterior perforated substance: the mammillary body, the interpeduncular fossa with the posterior perforated substance in it, the peduncles of the brain, the oculomotor nerves.
Access to the PPS area during surgery
The posterior communicating artery may obstruct the view and impair instrumental maneuverability during surgical intervention on the interpedicular fossa when the traditional pterional approach technique is realized. The traditional pterional approach for the surgical treatment of cerebral aneurysms was proposed by G. Yasargil. The technique performs an arcuate skin incision from the tragus to the midline along the border of the scalp and subsequent wide incision of the temporal muscle and craniotomy of the frontotemporal region9,17. To increase the working area, the posterior communicating artery can be separated (when it is hypoplastic) (Fig. 2). This innovation was presented by G. Yasargil based on 7 patients with aneurysm of the upper part of the basilar artery9,18. Subsequently, the division of the posterior communicating artery during surgical interventions was performed by other surgeons19,20,21.
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This method has been criticized because surgeons are concerned about the disturbance of blood flow in the perforating branches of the posterior communicating artery or the posterior cerebral artery. In addition, there is the risk of ischemia22,23,24. However, in the article “Dividing the posterior communicating fossa: technical aspects and safety” by Niklaus Krayenbühl, M.D., Ali F. Krisht, M.D., F.A.C.S. it was presented a review on a dividing of the posterior communicating artery demonstrated the safety of this procedure if it is carried out on the basis of the recommendations mentioned in the article by Niklaus Krayenbühl et al “Dividing the posterior communicating fossa: technical aspects and safety”, 2007.
Figure 2: Three options for dividing the PComA include cutting close to the P1–P2 junction (top for 88% of patients); dividing it in its middle segment (middle for 8% of patients), and cutting close to its branch from the internal carotid artery (bottom for 4% of patients).
Key: BA – basilar artery; ICA – internal carotid artery.
The interpeduncular nucleus (IPN) is situated in the PPS. The nucleus of the medial habenula (MHb) and the IPN form the dorsal conductive system of diencephalon that transmits signals from the limbic system to the diencephalon and hindbrain27. This pathway plays an important role in higher vertebrates in control of the activity of the mesencephalon and the reward mechanism28.
The nucleus of the MHb receives afferent signals from a variety of structures including the triangular septal nucleus, septofimbral nucleus, ventral tegmental area, and raphe nuclei29,30,31, nucleus accumbens28, locus coeruleus and superior cervical ganglion32, diagonal band nucleus and medial septum33, as well as the median raphe nucleus 28.34. According to multiple studies, the MHb may project to the pineal body and may send sparse efferents to the ventral tegmental area35.36. Nerve fibers also are directed from the IPN to the dorsal and medial suture nuclei37,38, as well as to the lateral habenula39,40. The main innervating source of the IPN is the nucleus of the medial habenula, with afferents arriving from the horizontal limbs of the diagonal band nucleus41, substantia innominata42, infralimbic region of the medial prefrontal cortex43, preoptic nucleus44, hypothalamic nuclei41,45, supra-mammillary nucleus41,45, raphe nuclei28, nucleus incertus45, and dorsal tegmental nucleus45 . All these projections are illustrated in the following figure 3:
Ian McLaughlin et al “The MHb and the IPN circuitry is critical in addiction, anxiety, and mood regulation”, 2017.
Designations: Red lines are the projection of the afferent signals, green lines are the projections of the efferent signals.
2- Septofimbrial nucleus.
10-Dorsal nucleus of the seam.
11-Medial nucleus of the seam.
14-Ventral tegmental area.
17-Nucleus of the diagonal strip.
19-Nucleus basalis of Meynert.
20-Bed nucleus of the anterior commissure.
The IPN and the MHb synthesize and release a large number of neurotransmitters. Numerous studies have found that acetylcholine46, substance P47,48,49, glutamate and GABA33, norepinephrine32, serotonin50,53 and many neuropeptides54,55 participate in the transmission of the signal by the dorsal conductive system of the diencephalon. In addition, this circuit has been shown to be involved in the mechanisms that mediate acute and aversive features of withdrawal from multiple drugs, including alcohol, opiates, nicotine, and other stimulants.
The MHb plays an important role in the development of depression56, in regulating the transmission of monoamine57, in various processes that suppress depression, control the sleep-wake cycle58, provide the reward mechanisms28, analgesia59,60 and behavioral inhibition61. According to the investigated data of the last 40 years, this nucleus affects marital behavior, hormonal response to stress, and nutritional behaviour62,28. J. S. Morris et al.63 found a relationship between the activity of the habenula and the degree of depression. Habenula removal completely blocks the development of helplessness64, raising the possibility that the habenula could be an effective therapeutic target in treatment-resistant depression.
The IPN, which gathers signals from the medial nucleus of the habenula41, also takes part in the development of helplessness when it becomes activated. Moreover, the IPN receives more acetylcholine than any other region in the mammalian brain65. This is interesting given evidence implicating excessive cholinergic tone in the etiology of depression66,67,68,69,70,71. Besides, increasing the duration of REM (rapid eye movement) sleep is a marker of endogenous depression72. The genesis of this phenomenon is that cholinergic agonists increase the drive for REM sleep73. Meanwhile lowering the activity of the interpeduncular nucleus reduces the duration of REM by 79%, without affecting other types of sleep58.
Thus, the forebrain controls the reward mechanism and the activity of the mesencephalon via connections between the IPN and the MHb28. The dorsal diencephalic conduction system plays an important role in the development of depression56, in regulation of the monoamine transmission57, also it is involved in various processes that suppress depression, control the sleep-wake cycle and reward mechanisms28, analgesia59,60 and behavioral inhibition61.
The posterior perforated substance is a triangular depression in the region of the mesencephalon. It consists of a gray matter and forms the bottom of the third ventricle. This area is of great interest for surgical interventions in patients with aneurysm of the upper part of the basilar artery. During surgical manipulation it is recommended that the posterior communicating artery be divided, which has been shown to be safe under certain conditions. The IPN is a special structure in the PPS that is involved in the “the medial nucleus of the habenula-IPN.” This review has described its neurophysiology, as well as correlation with various pathological dependencies, psychiatric conditions, mood, and impact on sleep. Future studies on the “medial habenula-interpeduncular nucleus” way may be useful for the development of drugs that affect this pathway to address various types of addictions and some mental diseases.
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The habenula is a complex nucleus composed of lateral and medial subnuclei, which connect between the limbic forebrain and midbrain.
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