cognitive impairment caused by subcortical lesion

Journal of Rehabilitation Neurosciences Vol. 19 2019 3

1　IntroductionThe gray matter tissues found on the outer surface of the cerebral hemisphere are collectively called the cerebral cortex. The gray matter comprises the neural tissue of the central nervous system and contains neuronal cell bodies. It has functional localization, such as the motor and sensory areas, as well as the association area of the cerebral cortex, which drives higher cognitive function［1,2］. In the cerebral hemispheres, the gray matter makes up the cortex. In addition to this, there is a mass of gray matter, called the gray nucleus, inside the cerebrum. The gray nucleus contains the caudate nucleus, the lens nucleus, the claustrum, and the amygdaloid nucleus. In comparison, the part of the brain that has no neuronal cell bodies and contains only myelinated nerve fibers is called the white matter, or medulla. It forms a large fibrous structure that occupies the area between the cortex and the gray nucleus, as well as between the ependyma. The brain’s white matter includes commissural fibers, such as the corpus callosum, that connect the left and right hemispheres; association fibers, such as the arcuate fasciculus, which connect different regions of the cerebral hemisphere on the same side; and projection fibers, such as the pyramidal tracts and optic radiation, which are found between the cerebral cortex and the underlying spinal cord. Clinicians usually refer to the white matter directly beneath the cerebral cortex as a “subcortical”

area. Anatomically, however, this term includes the brainstem, the cerebellum, the diencephalon, and the limbic system. This article discusses cognitive dysfunctions caused by these subcortical lesions.

2　Cognitive dysfunction and lesions2.1　 Cognitive dysfunction associated with lesions of the

basal gangliaThe basal ganglia are a collection of nuclei that connect the cerebral cortex with the thalamus and the brainstem. They comprise the striatum, the pallidum, the substantia nigra, and the subthalamic nucleus. Of these, the striatum, in particular, is involved with nerve processes such as motor functions and decision-making. A cerebral infarction of the striatum（striatocapsular infarction, SCI）is larger than typical lacunar infarctions that develop in the lenticulostriate arterial territory, which branches from the horizontal part of the middle cerebral artery （MCA）［3］, and is often caused by a cardiogenic or carotid lesion-derived embolus［4］. Even if the major artery is fully blocked, if collateral circulation or bypass is well developed, it becomes an SCI rather than an extensive cortical infarction （Figure 1）. Whether or not aphasia and unilateral spatial neglect appear depends on the duration of the MCA blockage and the degree of collateral circulation （leptomeningeal

Review Article

Cognitive impairment caused by subcortical lesion

Shinichiro MAESHIMA1*, Aiko OSAWA2

1. Kinjo University2. Department of Rehabilitation Medicine, National Center for Geriatrics and Gerontology

AbstractA variety of cognitive dysfunctions occur after subcortical damage. Aphasia and unilateral spatial neglect often result from lesions of the putamen and thalamus. They are particularly frequent during the acute stage of cerebral hemorrhage, with approximately 80% of patients presenting such symptoms. To understand the mechanism by which they appear, we must not only consider causes related to damage to the subcortical white matter fibers, but also secondary functional decline caused by direct damage to the cortex as well as by diaschisis. subtentorial lesions are known to cause language deficits, visuospatial inattention, executive function disorders, personal change, and other symptoms. Many of these reports pertain to cerebellar lesions; however, there are not a few cases where cognitive dysfunction develops because of brainstem lesions. Impairment of the cortical pontocerebellar tract’s fiber connections and damage to the brainstem reticular regulatory system may be considered as the mechanism by which cognitive dysfunction appears. Because of this, detailed cognitive function assessments must also be performed for patients with subtentorial.

Keywords: cerebrovascular disease, cognitive function, subtentorial lesion, subcortical lesion, cerebellar cognitive affective syndrome＊Correspondence: Shinichiro MAESHIMA, MD, PhD（[email protected]）, Kinjo University, 1200, Kasama-machi, Hakusan,

Ishikawa, 924-8511, Japan.Manuscript history: Received on 19 March 2019; Accepted on 15 April 2019.J-STAGE advance published date: 30 September 2019.doi: 10.24799/jrehabilneurosci.190319Citation: Maeshima S, Osawa A. Cognitive impairment caused by subcortical lesion. J Rehabil Neurosci. 2019; 19（1）: 3-9.

J Rehabil Neurosci4

Figure 1: CT scan and MRA in a patient with striatocapsular infarctionThe middle cerebral artery was completely occluded（arrow）, but as the collateral circulation or bypass was developed, the patient became SCI（striatocapsular infarction）without extensive cortical infarction. CT, computed tomography; MRA, magnetic resonance angiorgaphy.

Table 1: Cognitive dysfunction caused by striatocapsular infarction

AgeGender Etiology Days from

stroke onsetMonths of

hospital stay Visual field defect Brunnstrom stageU/E - L/E - finger Sensory deficit Cognitive

dysfunctions

71 M HT 14 6 present 2-2-1 present USN, CA, MI

67 F HD HL 6 6 2-2-1 present CA

71 M - 10 4 2-4-1 present USN, CA, MI

55 F HT 15 4 2-4-1 CA

64 M HT 4 8 3-3-2 present

65 F HT 2 6 2-2-1

58 M HT 25 5 2-2-2 Broca

76 M ICs 20 10 present 3-2-1 N.E. Broca

66 M HT DM 28 8 present 2-2-1 N.E. TGA BFA,IMA IA CA

57 F ASO DM 7 3 3-5-2 N.E. BrocaBFA CA

60 M HT 14 5 2-2-1

73 F HD 18 7 2-3-2 present

84 F HD 26 5 present 1-2-1 N.E. TGA BFA,IMA IA CA

72 F HT HD 24 9 present 1-1-1 N.E. TGA BFA,IMA IA CA

72 F HL ICs 7 7 present 2-2-1 N.E. TGA BFA,IMA IA CA

60 M HT ICs 12 8 2-2-2 N.E. Broca BFA

M, male; F, female; HT, hypertension; HD, hyperlipidemia; ICs, internal carotid artery stenosis; USN, unilateral neglect; CA, constructional apraxia; MI, motor impersistence; TGA, total global aphasia; BFA, buccofacial apraxia; IMA, ideomotor apraxia; IA, ideational apraxia, NE; not examined. Author translated from cited paper［6］.


anastomosis）［5］. Table 1 shows a list of SCI cases that we have previously reported［6］. Aphasia and apraxia occurred at high rates with left hemisphere lesions, and unilateral spatial neglect occurred with right hemisphere lesions. Although no differences related to the presence or absence of cognitive dysfunction in SCI were observed in nerve images, computed topographic electroencephalography of SCI accompanied by cognitive dysfunction showed few alpha waves and an abundance of slow waves（Figure 2）［7］.

With putaminal hemorrhage, on the other hand, if the volume of the hematoma is large, direct or edema-derived indirect pressure on the cortical field induces aphasia and unilateral spatial neglect. With aphasia, if the volume of the hematoma exceeds 20 mL, word repetition is impaired; if it exceeds 40 mL, speech fluency is lost（Figure 3）. Likewise, if the volume of the hematoma is less than 20 mL, unilateral spatial neglect is unlikely to develop; if it exceeds 40 mL, however, many of the symptoms persist. It should be noted,

however, that even if the volume of the hematoma exceeds 50 mL, some symptoms can disappear during the course of treatment in patients under the age of 50［8,9］. In brief, when considering a functional prognosis, we should consider not only the sites and sizes of the lesions but also the patient’s age. The following are being considered as the mechanism by which these cognitive dysfunctions appear:（1）disconnection of the subcortical white matter fibers,（2）cortical dysfunction that has developed because of pressure exerted by hematomas and edemas, and（3）a secondary decline in the function of the cerebral cortex.

2.2　 Cognitive dysfunction associated with thalamic lesionsThe thalamus is an egg-shaped mass of gray matter found in the upper part of the diencephalon. The dorsal side is covered with the cerebral hemisphere, and the ventral side, with the hypothalamus［10］. The thalamus projects numerous nerve fibers into the cerebral cortex. In other words, the thalamus relays sensory signals, except for olfaction, and projects them into the corresponding sensory field［11］. It also receives inputs from the cerebellum and basal ganglia, and projects them into the motor field of the cerebral cortex. It plays an important role in controlling posture and motor activity.

Thalamic hemorrhage often induces cognitive dysfunction such as aphasia and unilateral spatial neglect. During the acute stage of thalamic hemorrhage, in particular, aphasia is observed in 83% of patients with left lesions, and unilateral spatial neglect in 80% of patients with right lesions［12］. Patients who suffer aphasia associated with thalamic lesions produce little or no voluntary speech and speak in a soft voice. However, they make few grammatical errors and often show paraphasia, perseveration, and word-finding difficulties. Many have transcortical aphasia in which verbal repetition of sentence is maintained［13］. With thalamic hemorrhage, symptoms are observed with only a small hematoma volume. They appear to be caused not by direct pressure on the cortex, but by cortical dysfunction due to subcortical fiber damage or by diaschisis （Figure 4）［14］. Sometimes alexia with agraphia and pure

Figure 3: Relationship between hematoma volume and SLTA scoreWhen the hematoma volume exceeded 20 mL, the patients could not repeat. All patients whose hematoma volume exceeded 40 mL often showed non-fluent aphasia. SLTA, standard language test of aphasia. Cited from the author’s paper［8］.

Figure 2: Computed topographic electroencephalographic study in patients with striatocapsular infarctionComputed topographic electroencephalography of striatocapsular infarction accompanied by cognitive dysfunction showed few alpha waves and an abundance of slow waves. Cited from the author’s paper［7］.

J Rehabil Neurosci6

agraphia manifest with only a very small amount of hemorrhage localized in the thalamus［15,16］, so attention must be paid not to overlook these symptoms.

2.3　 Cognitive dysfunction associated with cerebellar lesionsThe cerebellum is involved in controlling the language faculties and mental functions that include cognition and thoughts. Damage to the cerebellum has long been known to cause cognitive dysfunction, such as impaired visuospatial ability［17］, mutism［18］, emotional disorders［19］, agrammatism［20］, and attention and executive function disorders［21］. Four main symptoms of cerebellar damage include executive function disorders, spatial disorder, social activity disorder, and speech impediment, and are collectively called cerebellar cognitive affective syndrome［22］.

Neuroanatomically, the cerebellum sends output not only to the cerebral motor f ield, but also to the prefrontal area and temporal lobe［23］. The presence of interconnections between the cerebellar hemisphere’s lateral part and the cerebral cortex’s lateral part of the motor area, the premotor area and prefrontal area or between the cerebellum’s intermediate part and the cerebral cortex’s total motor area, as well as the anatomical fiber connections between the vermis and prefrontal area （Brodmann area 46）, and the globus pallidus medial segment, are of growing scientific interest because they support the relationship between the cerebellum and cognitive functions, particularly with frontal lobe function［24,25］. A study using positron emission tomography （PET） and functional MRI （fMRI） with healthy subjects revealed that the cerebellum is activated during cognitive activities. In many of these cases, it is accompanied by activation of the frontal lobe in the opposite hemisphere, suggesting the involvement of the cross-type frontal lobe-cerebellar nerve fiber connection relating to cognitive function. Because of this, cognitive dysfunction seen following cerebellar damage is believed to be diaschisis,

which develops as a result of damage to the connections between the cerebellum and cerebral cortex. The phenomenon of this localized cerebellar lesion inducing a reduction in the circulation and metabolism of the cerebral hemisphere in the opposite side is called crossed cerebello-cerebral diaschisis and is believed to be a remote effect that is mediated by the cerebellar dentato-rubro-thalamic cortical tract［26,27］.

2.4　 Cognitive dysfunction associated with brainstem lesionsThe brainstem has long been understood to be involved with the reticular formation’s system that regulates consciousness and arousal, as well as the hypothalamic regulatory system［28］. In other words, the brainstem reticular formation becomes activated after receiving impulses from the ascending sensory pathway and activates the cerebral cortex via the thalamus and hypothalamus. From the hypothalamus, it sends stimulation to the limbic system, including the amygdaloid nucleus, the pyriform lobe, and the hippocampus, and at the same time, sends stimulation once again to the cerebral cortex via the midbrain. There is also anatomical knowledge that the brainstem possesses fiber connections with the association area of the cerebral cortex, and the thalamus-mediated afferent fibers project not only into the motor area but also into the dorsolateral prefrontal cortex （area 46）. Among the nerve fibers that connect the cerebral cortex and the cerebellum, the cortical pontocerebellar tract that is relayed by the bridge nuclei is the largest anatomical connection. Approximately half of the axons of nerve fibers that connect the cerebral cortex and the cerebellar hemispheres on the opposite side are thought to have a nerve terminal inside the bridge nucleus［29］. Since various cognitive functions are governed by a network that includes the brainstem of the cerebral hemisphere［30］, it is highly likely that cognitive dysfunction results from damage to the brainstem.

Clinically, researchers have noted that brainstem infarction causes areas of reduced local cerebral blood flow

Figure 4: CT scan（a）, SPECT（b）, and MRI tensor tractography（c） in patients with thalamic hemorrhageCognitive dysfunctions are observed with only a small hematoma volume in thalamic hemorrhage. They appear to be caused not by direct pressure on the cortex, but by cortical dysfunction due to subcortical fiber damage or by diaschisis. CT, computed tomography; SPECT, single photon emission computed tomography; MRI, magnetic resonance imaging.


not only subtentorially but also supratentorially in the frontal and parietal lobes ［31］. Evyapan et al.［32］reported on four patients who manifested denial of hemiplegia because of pontine infarction and stated that this was caused by a decline in frontal parietal subcortical activity resulting from brainstem damage. Garrard et al.［33］ studied cognitive disorders caused by pontine lesions and stated that executive function disorders, intellectual disorders, and other cognitive disorders occurred at a high rate. Hoffmann et al.［34］reported that more than half of 82 patients with a cerebral infarction that was localized either in the cerebellum or the brainstem presented some form of cognitive dysfunction. They also investigated five initial-onset stroke patients with lesions localized in the brainstem, and stated that all the subjects showed sites of reduced local cerebral blood flow in the frontal and parietal lobes and manifested cognitive dysfunction but had a favorable functional prognosis［35］. Cognitive dysfunction is involved in the functional prognosis of pontine infarction in addition to age, neurological symptoms, and dysphagia［36］.

3　Our cases with subtentorial lesionsFrom 1,153 patients with acute-stage cerebral infarction, we extracted 141 patients with cerebral infarction having subtentorial lesions, and we performed neuropsychological tests and cerebral blood flow examinations targeting 51 patients with pontine infarction and 20 with cerebellar infarction who were confirmed to have no other past illnesses or were not cases of recurrence and who had single-shot lesions. The results showed cognitive dysfunction in about half of all the subjects with both types of lesions（Figure 5）. The presence or absence of cognitive

dysfunction showed no differences related to the site or size of the loci, but was related to a reduction in local cerebral blood flow （Figure 6）. The possible mechanism by which this occurs is assumed to be the remote effects mediated by the cortical pontocerebellar tract and disorder of the brainstem reticular regulatory system. Cognitive dysfunction is seen during the early stage of onset, even with brainstem lesions; however, since it improves quickly, many cases go unnoticed unless they are carefully observed and evaluated. In actual clinical situations, moreover, patients complain of nausea and dizziness in addition to neurological symptoms such as motor paralysis and ataxia,

Figure 5: Cognitive dysfunction in patients with subtentorial lesionAbout half of the patients with cerebellar or brainstem lesion showed cognitive dysfunction. MMSE, mini-mental state examination; RCPM, Raven’s colored progressive matrices; FAB, frontal assessment battery.

Figure 6: Cognitive dysfunction and cerebral blood flow in patients with subtentorial lesionThe presence or absence of cognitive dysfunction was related to a reduction in local cerebral blood flow. MMSE, mini-mental state examination; RCPM, Raven’s colored progressive matrices; FAB, frontal assessment battery.

J Rehabil Neurosci8

making it difficult to evaluate cognitive function［36,37］. There is also a preconceived notion that infratentorial lesions do not cause cognitive dysfunction, which is another reason we believe the symptoms are often overlooked.

4　ConclusionWe suggest that detailed neuropsychological assessments must be performed for the patients because a variety of cognitive dysfunctions occur after subcortical damage.

5　AcknowledgmentsThis work was supported by“Research on Measures for Intractable Diseases” Project: matching fund subsidy from the Ministry of Health, Labour, and Welfare.

6　Conflicts of InterestThe authors have no conflicts of interest directly relevant to the content of this article.

References 1. Johnson KO, Gardner EP. Part V: Perception 21: Sensory

Coding. In: Kandel E, Schwartz J, Jessel T, Siegelbaum S, Hudspeth AJ, editors. Principles of Neural Science. 5th ed. New York: McGraw-Hill Education / Medical; 2012. p. 449-474.

2. Martin JH. Neuroanatomy Text and Atlas. 5th ed. New York: McGraw-Hill Education / Medical; 2012. p. 3-56.

3. Bladin PF, Berkovic SF. Striatocapsular infarction: large infarcts in the lenticulostriate arterial territory. Neurology. 1984; 34（11）: 1423-30.

4. Donnan GA, Bladin PF, Berkovic SF, Longley WA, Saling MM. The stroke syndrome of striatocapsular infarction. Brain. 1991; 114（Pt 1A）: 51-70.

5. Weiller C, Ringelstein EB, Reiche W, Thron A, Buell U. The large striatocapsular infarct. A clinical and pathophysiological entity. Arch Neurol. 1990; 47（10）: 1085-91.

6. Maeshima S, Nakai K, Itakura T, Komai N, Baba M, Kusudo M, et al.［A clinical study on the hemiplegic patients with striatocapsular infarction］. J Clin Rehabil. 1995; 4（8）: 798-803.

7. Kuno Y, Maeshima S, Baba M, Kusudo M, Dohi N. ［Cognitive dysfunction and computed electroencephalography in patients with striatocapsular infarction］. Ther Res. 16（6）: 1755-8.

8. Maeshima S, Okamoto S, Okazaki H, Funahashi R, Hiraoka S, Hori H, et al. Aphasia Following Left Putaminal Hemorrhage at a Rehabilitation Hospital. Eur Neurol. 2018; 79（1-2）: 33-7.

9. Maeshima S, Ueyoshi A, Matsumoto T, Boh-oka S, Yoshida M, Itakura T, et al. Unilateral spatial neglect in patients with cerebral hemorrhage: the relationship between hematoma volume and prognosis. J Clin Neurosci. 2002; 9（5）: 544-8.

10. Herrero MT, Barcia C, Navarro JM. Functional anatomy of

thalamus and basal ganglia. Childs Nerv Syst. 2002; 18（8）: 386-404.

11. Maeshima S, Osawa A. Thalamic Lesions and Aphasia or Neglect. Curr Neurol Neurosci Rep. 2018; 18（7）: 39.

12. Osawa A, Maeshima S. Aphasia and unilateral spatial neglect due to acute thalamic hemorrhage: clinical correlations and outcomes. Neurol Sci. 2016; 37（4）: 565-72.

13. Graff-Radford NR, Damasio H, Yamada T, Eslinger PJ, Damasio AR. Nonhaemorrhagic thalamic infarction. Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography. Brain. 1985; 108（Pt2）: 485-516.

14. Bogousslavsky J, Caplan LR. Vertebrobasilar Occlusive Disease: Review of Selected Aspects. Cerebrovasc Dis. 1993; 3: 193-205.

15. Osawa A, Maeshima S, Yamane F, Uemiya N, Ochiai I, Yoshihara T, et al. Agraphia caused by left thalamic hemorrhage. Case Rep Neurol. 2013; 5（1）: 74-80.

16. Maeshima S, Osawa A, Ogura J, Sugiyama T, Kurita H, Satoh A, et al. Functional dissociation between Kana and Kanji: agraphia following a thalamic hemorrhage. Neurol Sci. 2012; 33（2）: 409-13.

17. Wallesch CW, Horn A. Long-term effects of cerebellar pathology on cognitive functions. Brain Cogn. 1990; 14（1）: 19-25.

18. Kingma A, Mooij JJ, Metzemaekers JD, Leeuw JA. Transient mutism and speech disorders after posterior fossa surgery in children with brain tumours. Acta Neurochir. 1994; 131（1-2）: 74-9.

19. Pollack IF, Polinko P, Albright AL, Towbin R, Fitz C. Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery. 1995; 37（5）: 885-93.

20. Silveri MC, Leggio MG, Molinari M. The cerebellum contributes to linguistic production: a case of agrammatic speech following a right cerebellar lesion. Neurology. 1994; 44（11）: 2047-50.

21. Gottwald B, Wilde B, Mihajlovic Z, Mehdorn HM. Evidence for distinct cognitive deficits after focal cerebellar lesions. J Neurol Neurosurg Psychiatry. 2004; 75（11）: 1524-31.

22. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998; 121（Pt 4）: 561-79.

23. Middleton FA, Strick PL. The cerebellum: an overview. Trends Neurosci. 1998; 21（9）: 367-9.

24. Sasaki K, Jinnai K, Gemba H, Hashimoto S, Mizuno N. Projection of the cerebellar dentate nucleus onto the frontal association cortex in monkeys. Exp Brain Res. 1979; 37（1）: 193-8.

25. Middleton FA, Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science. 1994; 266（5184）: 458-61.


26. Rousseaux M, Steinling M. Crossed hemispheric diaschisis in unilateral cerebellar lesions. Stroke. 1992; 23（4）: 511-4.

27. Sönmezoğlu K, Sperling B, Henriksen T, Tfelt-Hansen P, Lassen NA. Reduced contralateral hemispheric flow measured by SPECT in cerebellar lesions: crossed cerebral diaschisis. Acta Neurol Scand. 1993; 87（4）: 275-80.

28. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949; 1（4）: 455-73.

29. Brodal A. Cerebrocerebellar pathways. Anatomical data and some functional implications. Acta Neurol Scand Suppl. 1972; 51: 153-95.

30. Sturm W, de Simone A, Krause BJ, Specht K, Hesselmann V, Radermacher I, et al. Functional anatomy of intrinsic alertness: evidence for a fronto-parietal-thalamic-brainstem network in the right hemisphere. Neuropsychologia. 1999; 37（7）: 797-805.

31. Rousseaux M, Steinling M, Mazingue A, Benaim C, Froger J. Cerebral blood flow in lateral medullary infarcts. Stroke. 1995; 26（8）: 1404-8.

32. Evyapan D, Kumral E. Pontine anosognosia for hemiplegia. Neurology. 1999; 53（3）: 647-9.

33. Garrard P, Bradshaw D, Jäger HR, Thompson AJ, Losseff N, Playford D. Cognitive dysfunction after isolated brain stem insult. An underdiagnosed cause of long term morbidity. J Neurol Neurosurg Psychiatry. 2002; 73（2）: 191-4.

34. Hoffmann M, Schmitt F. Cognitive impairment in isolated subtentorial stroke. Acta Neurol Scand. 2004; 109（1）: 14-24.

35. Hoffmann M, Watts A. Cognitive dysfunction in isolated brainstem stroke: a neuropsychological and SPECT study. J Stroke Cerebrovasc Dis. 1998; 7（1）: 24-31.

36. Maeshima S, Osawa A, Miyazaki Y, Takeda H, Tanahashi N. Functional outcome in patients with pontine infarction after acute rehabilitation. Neurol Sci. 2012; 33（4）: 759-64.

37. Maeshima S, Osawa A, Kunishio K. Cognitive dysfunction in a patient with brainstem hemorrhage. Neurol Sci. 2010; 31（4）: 495-9.

cognitive impairment caused by subcortical lesion

Documents