a protocol for manual segmentation of the human …...an introduction to its functional anatomy, 5th...

A protocol for manual segmentation of the human thalamus on T1

weighted MRI scans

Australian United States and Scandinavian Imaging Exchange

Authors • Dr Brian D. Power, Neuropsychiatrist, School of Medicine, The University of Notre Dame Australia, Fremantle,

Australia; Research Associate at the Clinical Research Centre, North Metropolitan Health Service - Mental Health, WA, Australia.

• Ms Fiona A. Wilkes, Medical and PhD student, Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, Australian National University Medical School, Canberra Hospital, Canberra, ACT, Australia.

• Mr Mitchell Hunter-Dickson, Medical student, Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, Australian National University Medical School, Canberra Hospital, Canberra, ACT, Australia.

• Dr Danielle van Westen, Chief of Neuroradiology, Center for Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden & Diagnostic Radiology, Department of Clinical Sciences, Lund University, Lund, Sweden.

• Dr Alexander Santillo, Registrar in Psychiatry, Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.

• A/Prof Mark Walterfang, Neuropsychiatrist, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, and University of Melbourne, Melbourne, Australia.

• Christer Nilsson, Neurologist and Chair of Geriatric Psychiatry, Center for Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden & Diagnostic Radiology, Department of Clinical Sciences, Lund University, Lund, Sweden.

• Prof Dennis Velakoulis, Neuropsychiatrist and Director, Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, and University of Melbourne, Melbourne, Australia.

• A/Prof Jeffrey C.L. Looi, Neuropsychiatrist and Deputy Head, Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, Australian National University Medical School, Canberra Hospital, Canberra, ACT, Australia.

Validation We present a validated protocol for manual segmentation of the thalamus on T1-weighted magnetic resonance imaging (MRI) scans using brain image analysis software. The MRI scans of five normal control subjects were randomly selected from a larger cohort recruited from Lund University Hospital and Landskrona Hospital, Sweden. MRIs were performed using a 3.0T Philips MR scanner, with an eight-channel head coil, and high resolution images were acquired using a T1-weighted turbo field echo (T1 TFE) pulse sequence, with resulting voxel size 1 x 1 x 1mm3. Manual segmentation of the left and right thalami and volume measurement was performed on 175 contiguous coronal slices, using ANALYZE 11.0 software. Reliability of image analysis was performed by measuring intra-class correlations between initial segmentation and random repeated segmentation of the left and right thalami in 5 subjects (yielding 10 thalami for segmentation); inter-rater reliability was measured using volumes obtained by two other experienced tracers. The protocol had sound intra-rater and inter-rater reliability. The validated protocol can be used for any image analysis software capable of displaying images in three orthogonal planes. We anticipate that mapping thalamic morphology in various neuropsychiatric disorders may yield clinically useful disease-specific biomarkers.

Table showing intra-rater and inter-rater reliability data

Correlation 95%CI

F Test true

value

p value

Intraclass correlation

(Tracer 1) 0.95 0.79-0.99 51.35 <0.01

Intraclass correlation

(Tracer 2) 0.98 0.92-0.99 115.76 <0.01

Interclass correlation

(Tracer 1 and 2) 0.92 0.80-0.97 22.48 <0.01

Interclass correlation

(Tracer 1 and 3) 0.98 0.92-0.99 90.57 <0.01

Use of anatomical terms rostral and caudal

• Caudal and rostral are used as terms of reference

• In the coronal plane, the term rostral (“situated toward the nose”) is used to refer to the more anterior structure.

• In the coronal plane, the term caudal (“situated toward the tail”) is used to refer to the more posterior structure.

Protocol development and thalamic boundary definition

• The protocol was designed by a neuropsychiatrist with extensive experience in the clinical neuroanatomy of the thalamus (BDP), and with reference to neuroradiological and neurosurgical atlases (Duvernoy, 1999; Morel, 2007).

• Manual segmentation of the dorsal thalami (left and right) occurred in 28-30 consecutive 1mm coronal slices (from an average of 175 coronal slices of the human brain).

• The protocol proceeds in a caudal to rostral direction (intercommissural plane), starting by tracing the pulvinar as it emerges under the crus fornix, and then proceeding rostrally until the crus cerebri can be seen separating from the body of the pons.

• The medial border was defined by the third ventricle, and superior cistern in more caudal sections.

• The lateral border is defined by the reticular thalamic nucleus (of the ventral thalamus).

• The inferior border was defined at various levels by using either nearby landmarks (e.g., habenular), characteristic white matter tracts proximal to prominent landmarks (i.e., those adjacent to the red nucleus, and subthalamic nucleus), and in more rostral sections the hypothalamic sulcus (hypothalamus, column of fornix).

• The superior border was defined by the body of the lateral ventricle.

• The most rostral slices are challenging, characterized by the emergence of the mammillary bodies and hypothalamus. In the most rostral slice the thalamus is visualized at the inferior pole of the head of the caudate, 5-6mm caudal to the anterior commissure - a prominent landmark.

• The protocol attempts to utilize the ventral thalamus (including the reticular thalamic nucleus and zona incerta) for boundary definition, and hence exclude these structures from tracing where possible.

Intensity Loaded Volume – Region of Interest function

• Using ANALYZE 11.0 the Intensity Loaded Volume - Region of Interest function was utilized to optimize intensity settings, thereby enhancing contrast between gray and white matter, and assist in boundary definition (minimum value: 50-100; maximum value: 500-600). In addition, the Invert function (making white matter appear dark) was utilized to facilitate boundary definition on every slice. Each individual slice is presented in the protocol in duplicate, the first image demonstrating thalamic boundary definition for the slice, and the second image is the same slice with intensity settings inverted.

• ANALYZE 11.0 software settings: – Intensity Loaded Volume – Region of Interest function (from the tool bar)

– select “window” for Type, select “Max/Min” and set minimum value to 50-100 and maximum value to 500-600; select Range.

– Utilizing the INVERT function during segmentation (making white matter appear dark) is particularly useful to enhance white matter in defining the inferior thalamic border in more rostral slices

Additional information

• Surface mapping

• For the purposes of surface mapping, that portion of the lateral geniculate nucleus that becomes separated from the main body of the thalamus can be excluded from segmentation

• This would be applicable to the following slices presented here: slices 13,14,15

• Resources

• Recommended atlases are Duvernoy (1999) and Morel (2007)

• There is also reference to other resources including Haines (1991), Nolte (2002) and Roberts and Hanaway (1971).

• Note Duvernoy brain slices are 2mm thick (MR images are less reliable)

• Each figure referenced in Morel contains two drawings of thalamic sections, and intervals between sections are 1mm (corresponding to 1mm in vivo); drawings are identified relative to the posterior commissure (A=anterior, P= posterior; eg A3 = 3 mm anterior to the posterior commissure), with an intercommissural distance of 26mm.

References

Duvernoy HM (1999) The Human Brian: Surface, Three-Dimensional Sectional Anatomy and MRI, 2nd edition. New York: Springer-Verlag. Haines DE (1991) Neuroanatomy: An Atlas of Structures Sections and Systems. Baltimore: Urban and Schwarzenberg. Nolte J (2002) The Human Brain. An introduction to its functional anatomy, 5th edition. London: Mosby. Morel A (2007) Stereotactic atlas of the human thalamus and basal ganglia. New York: Informa healthcare USA, Inc. Roberts MP and Hanaway J (1971) Atlas of the human brain in section. Philadelphia: Lea and Fibiger.

Orientation to the region of interest (the caudal thalamus)

• Identify the most caudal part of the thalamus (the pulvinar) in an axial or horizontal section (e.g. Duvernoy 1999, Fig 200, p570) OR, in a coronal plane, identify the cerebellum and the first appearance of the superior colliculus, scrolling in a rostral direction (Duvernoy, Fig 80, p160)

• The protocol proceeds in a caudal to rostral direction, given the relative ease of thalamic boundary definition in the most caudal slices, and the more challenging definition of thalamic boundary in the most rostral slices.

One slice caudal to thalamus

REFERENCES DESCRIPTION OF THALAMIC BOUNDARY AND RELATED STRUCTURES VENTRICULAR SPACES

Duvernoy (1999) Fig 78-

79 p156-158

Roberts and Hanaway

(1971) p31

The pulvinar of the thalamus is not yet discernible. The splenium of the corpus

callosum is a characteristic feature at this level. The colliculi may be noted and

followed rostrally (as the pons becomes visible); cerebellar lobes and cerebellar

peduncles are prominent. The hippocampus is present throughout much of the

caudal-rostral extent of the thalamus, except in the most rostral slices where the

amygdala is prominent.

The temporal horn of the

lateral ventricle (LV) is

contiguous with body of the LV

(shaped like a tear drop). The

atrium of the ventricle appears

in more caudal slices.

Slice 1


Duvernoy (1999)

Fig 77 p154

Haines (1991) Fig

5-27 p122; Fig 4-13

p59

The oval-shaped pulvinar of the thalamus can just be visualized between

the crus fornix and the superior cistern. The pineal gland can be seen

centrally, superior to the colliculi. The diagonal crossing of the crus fornix

and splenium of the corpus callosum is a characteristic feature. The crus

fornix can be seen merging with the posterior part of the hippocampal

formation; note the parahippocampal gyrus and subiculum.

The LV appears distinct from the

temporal horn of the LV. The superior

cistern (or quadrigeminal cistern/ cistern

of the great cerebral vein) is prominent

in these more caudal sections (it is a

radiological landmark above the

midbrain in the horizontal plane)

Slice 2


Duvernoy (1999) Fig

77 p154

Haines (1991) Fig 5-

27 p122; Fig4-13 p59

The oval-shaped pulvinar of the thalamus can be clearly visualized between the

crus fornix and the superior cistern. As per slice 1

Slice 3


Duvernoy (1999)

Fig 76-77 p152-154

Roberts and

Hanaway (1971)

p29

The pulvinar is a distinct mass of grey matter visualized under the corpus

callosum, and between the fornix and the superior cistern. Note its location

relative to the parahippocampal gyrus and hippocampus. The midbrain has

not merged with the thalamus; the pineal gland can still be seen centrally,

superior to the quadrigeminal plate (superior and inferior colliculi). The

caudate can be seen at the lateral edge of LV.

The LV is well demarcated. The temporal

horn of LV is seen adjacent to the

hippocampus. The median sulcus of the

of the midbrain is defined by CSF; in

more rostral sections this appears to

merge with the central aqueduct.

Slice 4


Duvernoy (1999) Fig

76-77 p152-154

Roberts and Hanaway

(1971) p29

The pulvinar is a distinct mass of grey matter visualized under the corpus callosum,

and between the fornix and the superior cistern. As per slice 3.

Slice 5


Duvernoy (1999), Fig 76 p152

Roberts and Hanaway (1971)

p29

The pulvinar is well demarcated and seen enlarging laterally in more

rostral slices; its lateral border is defined by the internal capsule.

The median sulcus of the of the

midbrain appears to merge with

the central aqueduct.

Slice 6


Duvernoy (1999)

Fig 75 p152

Morel (2007) Fig

4.1 p56

The thalamus is becoming continuous with the midbrain; its inferior and lateral

borders are easily defined, as above. A vertical line from the caudate serves as a

guide for defining the lateral extremes of the thalamus. Thus far the thalamus has

maintained an oval shape; in more rostral sections the presence of the geniculates

will cause the inferior border to bulge laterally. Note the size of the heads of the

caudate, as it enlarges in more rostral slices.

The LV clearly defines the superior

border of the thalamus. The superior

cistern appears enclosed in these

sections by the thalamus and the

midbrain. The central aqueduct is

evident.

Slice 7


Duvernoy (1999) Fig 74-75 p148-152

Morel (2007) Fig 4.2 p57

Roberts and Hanaway (1971) p27

The appearance of the geniculates cause the inferior thalamic border to

bulge laterally (the commissure of superior colliculi may be seen). As per slice 6.

Slice 8


Duvernoy (1999) Fig 74-75 p148-152

Morel (2007) Fig 4.2 p 57


The appearance of the geniculates cause the inferior thalamic border to

bulge laterally; the lateral geniculate is forming a distinctive lateral

protuberance.

As per slice 7.

Slice 9


Duvernoy (1999) Fig 74 p148

Morel (2007) Fig 4.2-4.3 p 57-p58


Haines (1991), Fig 4-12 p58

Nolte (2002) Fig 24-9 p602

A key feature is the posterior commissure, and the emergence of other

thalamic nuclei in addition to the pulvinar. The medial and lateral geniculate

bodies of the thalamus form its inferior border; the thalamic mass is enclosed

by the curved shell of the reticular thalamic nucleus laterally; the lateral

border is the internal capsule. The habenular nucleus emerges, producing a

noticeable bulge on the midline. An oblique line from the habenular directed

in an inferior-lateral direction at approximately 45 degrees (towards the

subiculum) marks the inferior-medial border of the thalamus at this level.

Superior to the posterior

commissure, the superior

cistern defines the medial

border of the thalamus;

inferior to the

commissure is the

cerebral aqueduct.



Morel (2007) Fig 4.2-4.3 p 57-p58


Haines (1991) Fig 4-12 p58

Nolte (2002) Fig 24-9 p602

As per slice 9. As per slice 9.

Slice 10

Slice 11



Morel (2007) Fig 4.3 p58

The thalamus mass is well defined. An oblique line from the habenular

defines the inferior-medial border. The lateral border is the internal

capsule.

The LV and 3V respectively define

the superior and medial borders of

the thalamus.

Slice 12


Duvernoy (1999)

Fig 72 p144

Morel (2007) Fig

4.3-4.4 p58-59

The medial dorsal nucleus of the thalamus abuts the third ventricle (3V); the

medial and lateral geniculates comprise the inferior thalamic mass. The lateral

geniculate forms a protrusion from the rounded thalamic mass. The reticular

thalamic nucleus cloaks the lateral aspect, with the lateral border defined by the

internal capsule. The superior colliculus is no longer visible.

The LV and 3V respectively define

the superior and medial borders of

the thalamus.

Slice 13

REFERENCES DESCRIPTION OF THALAMIC BOUNDARY AND RELATED STRUCTURES VENTRICULAR

SPACES

Duvernoy (1999) Fig 71

p144

Morel (2007), Fig 4.4

p59

The lateral aspect of the thalamus is now defined by the ventral posterior nucleus (the pulvinar is

no longer evident). The habenular is less visible; to delineate the thalamus from the brainstem in

subsequent sections, draw a line from the hypothalamic sulcus of 3V to the medial edge of the

geniculate complex. The lateral geniculate nucleus is adjacent to the large thalamic mass, and

becoming separated from it (the medial geniculate is less distinct). The substantia nigra and

cerebral peduncle are becoming evident within the pons.

As per slice 12.

Slice 14


SPACES

Duvernoy (1999)

Fig 70-71 p142

Morel (2007) Fig

4.4 p59

Nolte (2002), Fig

16-13 p395

The red nucleus is a characteristic rounded feature at this level, superior to the substantia nigra and

cerebral peduncle, and inferior to the thalamic mass. Various slender white matter tracts can be seen

in subsequent rostral sections between the red nucleus and the inferior border of the thalamic mass,

and the contrast provides a useful guide for boundary definition until the hypothalamus emerges. The

putamen can not yet be visualized. The lateral geniculate nucleus is clearly separated from the greater

thalamic mass by the internal capsule/ cerebral peduncle ; the medial geniculate is no longer evident.

A line between the lateral geniculate and caudate approximates the lateral thalamic boundary.

.As per slice

13.

Slice 15


Duvernoy (1999), Fig 70 p140

Morel (2007) Fig 4.5, p60

The reticular thalamic nucleus forms a shell around the lateral thalamic border, and

is continuous with the zona incerta inferiorly. The red nucleus is a prominent and

guides the definition of the inferior thalamic border. The putamen is visible as a

lateral nuclear mass.

As per slice 13.

Slice 16



p138

Morel (2007) Fig 4.5-

4.6 p60-61

The two thalami can be seen to abut in the midline at the interthalamic adhesion (or massa

intermedia). The lateral geniculate nucleus is diminutive and can be difficult to identify,

superior and medial to the hippocampus (not traced in this case on the right). The

subthalamic nucleus emerges inferiorly to the zona incerta, and forms a medial

continuation of the reticular thalamic nucleus-zona incerta shell (lateral to the red

nucleus).

The massa intermedia

may be identified at

this level.

Slice 17


Duvernoy (1999) Fig

69 p138

Morel (2007) Fig 4.6

p61

The rounded mass of the thalamus is distinctive and bounded by white matter

laterally and inferiorly. The two thalami abutting in the midline together have a

characteristic “heart-shaped” appearance. The putamen is well visualized at this

level.

Tracing of the medial boundary

includes only the superior border of

3V. The interpeduncular fossa may

emerge in this slice.

Slice 18


Duvernoy (1999) Fig

68 p136

Morel (2007) Fig 4.6,

p61

The lateral geniculate nucleus has been replaced by the optic tract at this level. The globus

pallidus is emerging medial to the putamen. The red nucleus and associated white matter

tracts remain useful landmarks for definition of the inferior thalamic border; a vertical line

from the caudate serves to approximate the lateral thalamic boundary, which is bounded

by the internal capsule.

The interpeduncular fossa

will be evident at this

level.

Slice 19


SPACES


Morel (2007) Fig 4.7 p62

Haines (1991) Fig 4-11 p57

Nolte (2002) Fig 16-12 p395

Roberts and Hanaway (1971)

p23

The thalamic mass is well demarcated in this slice (bilaterally yielding a distinctive

“heart-shaped” appearance). The superior border of the red nucleus and associated

white matter tracts identifies the inferior border of the thalamus. The globus pallidus

(external segment) is clearly evident. The caudate enlarges in subsequent rostral

sections (a vertical line from it approximates the lateral limit of the thalamus).

As per slice 18.

Slice 20



p132

Morel (2007) Fig 4.7-

4.8 p62-63

Roberts and Hanaway

(1971) p21

The rounded thalamic mass is largely comprised of the medial dorsal and ventral lateral

thalamic nuclei, and the anterior thalamic nucleus is emerging. The red nucleus is

becoming less prominent and will no longer aide with defining the inferior thalamic

border at more rostral levels. The zona incerta/ subthalamic nucleus become important

guides in the following rostral slices. The striatum is becoming more prominent. The

optic tract can be seen medial to the temporal stem, and should be followed from this

point for its relation to the mammillary bodies in the most rostral thalamic slices.

Note the LV, inferior/

temporal horn of the LV,

and interpeduncular

fossa.

Slice 21


SPACES

Duvernoy (1999) Fig 66-

65 p132-130

Morel (2007) Fig 4.8 p63

Haines (1991) Fig 5-32

p132

The red nucleus is no longer visible to serve as a landmark; identify the subthalamic nucleus

superior to the substantia nigra. White matter tracts enveloping the medial aspect of the

zona incerta/ subthalamic nucleus aide with identification of the inferior thalamic

boundary. Within the thalamic mass, the ventral anterior thalamic nucleus emerges in place

of the ventral lateral nucleus. Note the uncus of the hippocampus.

As per slice 20.

Slice 22


Duvernoy (1999), Fig 65

p130

Morel (2007), Fig 4.8-4.9

p64

Note the emergence of the mammillothalamic tract as it extends through the thalamic

mass in subsequent sections. The thalamic mass becomes smaller in subsequent

rostral sections, receding superiorly towards the lateral ventricle. Note the size of the

lentiform nucleus (globus pallidus/ putamen).

As per slice 20.

Slice 23


Duvernoy (1999)

Fig 64 p128

Morel (2007) Fig

4.9-4.10 p64-65

The subthalamic nucleus is only just evident at this level, and the zona incerta

merges with the hypothalamus at its medial border. The thalamic mass is

adjacent to the top half of the third ventricle, whilst the hypothalamus is

adjacent to the bottom part (defining the hypothalamic sulcus).

Note the hypothalamic sulcus of 3V,

and the interpeduncular fossa.

Slice 24


Duvernoy (1999)

Fig 64 p128

Morel (2007) Fig

4.9-4.10 p64-65

As per slice 23. The crus cerebri can be seen separating from the body of the

pons at this level.

The interpeduncular fossa is only

just bounded by the receding crus

Slice 25



Morel (2007) Fig 4.10 p65


The crus cerebri have separated from the body of the pons. The

mammillary bodies will appear to emerge from the hypothalamus in

rostral sections. As an approximation, the lateral edge of the thalamus

overlaps the medial border of the caudate. The subthalamic nucleus is no

longer evident.

LV and 3V are becoming

more prominent and assist

in boundary definition.

Slice 26


Duvernoy (1999)

Fig 62-63, p124-126

Morel (2007) Fig

4.11, p66

The hypothalamus abuts the inferior portion of the third ventricle in the midline. The

thalamus is seen superiorly to this, and is well defined laterally by the internal capsule;

the major nuclei within the thalamus are now the ventral anterior and anterior thalamic

nuclei. The mammillary bodies are distinct, and seen medial and adjacent to the optic

tract The caudate enlarges in subsequent rostral sections.

As per slice 25

Slice 27


SPACES


p124

Morel (2007) Fig 4.11-4.12

p66-67

Nolte (2002) Fig 16-11 p394

The thalamus continues to become more discrete in size, and appears to recede towards

the lateral ventricle; the superior lateral tip of the thalamus abuts the inferior medial tip

of the caudate. The hypothalamus forms much of the medial border of the third

ventricle. The mammillary bodies are prominent. The column of the fornix emerges within

the hypothalamus and will become a prominent white matter feature in the mid line at

more rostral levels.

As per slice 25.

Slice 28


SPACES


p122

Morel (2007) Fig 4.12 p67

Nolte (2002) Fig 16-10

p394.

Roberts and Hanaway

(1971) p15

The thalamic mass abuts the inferior edge of the caudate (thalamic volume is similar to that of

the caudate in the most rostral thalamic sections). The anterior thalamus rests on the third

ventricle at the midline. Its lateral border is the genu of the internal capsule. The optic tract

appears closer to the midline. The mammillary bodies diminish at this level; the thalamus,

although difficult to visualize in this slice, is still present just rostral (1-2mm) to where the

mammillary bodies can no longer be visualized. The column of the fornix is prominent. The

amygdaloid complex is becoming more prominent and superior to the curved/ re-curved

hippocampal structure that has characterized previous caudal sections.

As per slice

25.

Slice 29


Duvernoy (1999)

Fig 60-61 p120-122

Morel (2007) Fig

4.12-13 p67-68

The most rostral thalamic level is the most difficult to define; it is found at the inferior pole

of the caudate. The hypothalamus protrudes inferiorly, immediately adjacent to the optic

tract. The mammillary bodies are no longer evident. The amygdala is seen in place of the

hippocampus. The column of the fornix becomes more prominent, and can be followed

through in subsequent rostral sections to be found superior to the anterior commissure

-

One slice rostral to thalamus



Morel (2007) Fig 4.13-4.14 p68-

69

Note the distinctive column of the fornix, and its more medial and superior

location in these rostral slices where no thalamic mass is evident. The

hypothalamus and optic tract protrude inferiorly.

-

Orientation to rostral thalamus: anterior commissure


Duvernoy (1999)

Fig 57, p114

Morel (2007) Fig

4.15-4.16, p70-71

Identify the anterior commissure (and follow the striatum through sections in a caudal

direction to locate the rostral pole of the thalamus). Note the column of the fornix, the

optic chiasm and the location of the hypothalamus in this section (follow these

structures in the subsequent sections). The most rostral portion of the thalamus will

emerge approximately 5-6mm caudal to the anterior commissure.

Note the frontal horn of LV

and suprachiasmatic recess

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