Brain SPECT scans in students with specific learning disability: Preliminary results.

Background and
Objectives: Brain single-photon emission computed tomography (SPECT) assesses brain function through measurement of regional cerebral blood flow. This study was conducted to assess whether students with newly diagnosed specific learning disability (SpLD) show any abnormalities in cerebral cortex perfusion. Settings and Design: Cross-sectional single-arm pilot study in two tertiary care hospitals. Subjects and
Methods: Nine students with SpLD were enrolled. Brain SPECT scan was done twice in each student. For the first or "baseline" scan, the student was first made to sit with eyes open in a quiet, dimly lit room for a period of 30-40 min and then injected intravenously with 20 mCi of 99mTc-ECD. An hour later, "baseline scan" was conducted. After a minimum gap of 4 days, a second or "test scan" was conducted, wherein the student performed an age-appropriate curriculum-based test for a period of 30-40 min to activate the areas in central nervous system related to learning before being injected with 20 mCi of 99mTc-ECD. Statistical Analysis Used: Cerebral cortex perfusion at rest and after activation in each student was compared qualitatively by visual analysis and quantitatively using NeuroGam™ software.
Results: Visual analysis showed reduction in regional blood flow in temporoparietal areas in both "baseline" and "test" scans. However, when normalization was attempted and comparison done by Talairach analysis using NeuroGam software, no statistically significant change in regional perfusion in temporoparietal areas was appreciated.
Conclusion: Brain SPECT scan may serve as a robust tool to identify changes in regional brain perfusion in students with SpLD.

Introduction

Specific learning disability (SpLD) is a group of neurodevelopmental disorders which manifest in childhood as persistent difficulties in learning to efficiently read (“dyslexia“ or “SpLD1“), write (“dysgraphia“ or “SpLD2“), and/or perform mathematical calculations (“dyscalculia“ or “SpLD3“), despite normal intelligence, conventional schooling, intact hearing and vision, and adequate motivation and sociocultural opportunity.[1] Up to 5%–10% of “seemingly normal“ school children have this hidden disability.[1] Dyslexia affects 80% of all those identified as learning-disabled.[1] The precise etiology of SpLD remains controversial but it is believed to be a result of functional problem with brain “wiring“ rather than an anatomic problem and is genetically inherited.[2]

Brain single-photon emission computed tomography (SPECT) is a well-established and reliable method to assess brain function through measurement of regional cerebral blood flow (rCBF).[3] We conducted this study to assess whether Indian students with newly diagnosed SpLD show any abnormalities in cerebral cortex perfusion.

Subjects and Methods

Ethics

This study was approved by both the institutional ethics committees. The study protocol is registered with clinical trials registry of India (CTRI/2017/09/009757). An accompanying parent or legal guardian signed an informed consent form permitting participation of his or her offspring. In addition, all school students signed an assent form before enrolment. Confidentiality was maintained using unique identifiers.

Design, setting, and sample size

The present cross-sectional single-arm study was carried out jointly in two tertiary care hospitals in Mumbai, a megacity in western India from July 2013 to December 2014. Being a pilot study, no sample size calculations were made.

Inclusion criteria and enrolment process

The study population comprised students 8–18 years of age who were newly diagnosed with SpLD (“one or more of these three disabilities,“ namely, SpLD1 ± SpLD2 ± SpLD3). All students in the study group were right-handed and studying in English-medium schools situated in the city of Mumbai. Exclusion criteria were students with newly diagnosed SpLD who had a history of central nervous system (CNS) infection or comorbid epilepsy or those who were already on any medication for their comorbid ADHD.

Diagnosis of SpLD

Only children above 8 years of age were included in the study as a conclusive diagnosis of SpLD cannot be made before that age.[4] Each student underwent standard recommended psycho-educational evaluation before the diagnosis of SpLD was confirmed.[4] Hearing and visual hearing deficits of >40% were ruled out by an otolaryngologist and an ophthalmologist, respectively. The counsellor ruled out whether any environmental deprivation due to poor home or school environment, or any emotional problem was primarily responsible for a child's poor school performance. Wechsler Intelligence Scale for Children-Revised (M.C. Bhatt's Indian adaptation) was used to determine whether a student's global intelligence quotient score was average or above average (≥85).[45] Using a locally developed and validated English curriculum-based test, the Special Educator conducted educational assessment in specific areas of learning, namely, basic learning skills, reading comprehension, oral expression, listening comprehension, written expression, mathematical calculation, and mathematical reasoning.[6] Based on this test, an academic underachievement of up to 2 years below the student's actual school grade placement or chronological age led to a diagnosis of SpLD.[46]

Using information from the child's parents and teachers, diagnosis of co-occurring attention-deficit/hyperactivity disorder (ADHD), if present, was made by ascertaining that student's specific behaviors met the required Diagnostic and Statistical Manual of Mental Disorders-IV-revised (DSM-IV-R) criteria.[7] Up to 40%–46% of children with SpLD have associated ADHD which is characterized by persistent hyperactivity, impulsivity, and inattention and this comorbidity further impairs their learning.[89]

Data collection

For each student, brain SPECT scan was done twice, with a minimum gap of 4 days between the two scans. Both scans were conducted with the student not having performed any academic activity, namely, reading, writing, or mathematics on that day prior to the scan. For the first or “baseline“ scan, the student was made to sit with eyes open in a quiet, dimly lit room for a period of 30–40 min and then injected intravenously with 20 mCi of99m Tc labelled L, L-ethylcysteinate dimer (99m Tc-ECD), which has been widely used to study changes in relative rCBF using SPECT systems.[310] This technique is called brain perfusion, and it relies on the coupled behaviour of blood flow and metabolism, which is used as a marker of neuronal activity.[310] An hour later, the student was imaged on a dual-headed GE Infinia Hawkeye SPECT/CT.

For the second or “test scan,“ the student was made to perform age-appropriate curriculum-based test[6] under the supervision of the Special Educator for a period of 30–40 min to activate the areas in CNS related to reading, writing, and doing mathematical calculations. Subsequently, the student was injected intravenously with the same dose of ECD. Similarly, an hour later “test scan“ was conducted.

Data analysis

Initially, qualitative assessment using visual analysis was conducted to assess and compare cerebral cortex perfusion at rest (“baseline scan“) and after activation (“test scan“) in each student. Subsequently, quantitative assessment was performed using NeuroGam™ software (GE Medical System, Segami Corp., Columbia, MD, USA) to find out whether there were any statistically significant changes in the four different lobes – frontal, parietal, temporal, and occipital in both hemispheres [Figure 1]. NeuroGam statistical software for automated diagnosis of brain perfusion SPECT images uses an affine anatomical coregistration by blocks of data defined in Talairach space. It is used to investigate rCBF objectively and easily in cerebral lobes of left and right hemispheres.[11]

Figure 1

Pre- and post-activation 99mTc ECD brain SPECT–Talairach analysis study in an SpLD student; (a) trans-axial images of baseline scan; (b) trans-axial images of test scan; (c) delta (a normalized subtraction of counts of baseline and test) images using NeuroGam (Talairach) analysis; (d) baseline (early) and test (late) trans-axial brain images, (e) graph showing an apparent increase in perfusion in all segments of test image based on the counts obtained in regions

Results

Qualitative assessment using visual analysis showed reduction in regional blood flow both in “baseline scans“ and “test scans“ in temporoparietal areas in all nine students [Table 1a]. However, when normalization was attempted and comparison was done by Talairach analysis using NeuroGam software, no statistically significant change in regional perfusion in temporoparietal areas was appreciated [Table 1b].

Table 1a

Clinical characteristics and qualitative assessment using visual analysis of cerebral cortex perfusion pattern at rest (“baseline scan”) and after activation (“test scan”) in the study sample

Patient no.	Age	Gender	Type of SpLD	Comorbidity	Baseline scan	Test scan
					Lobe(s) with minimum perfusion	Lobe(s) with minimum perfusion
1	9 yrs. 2 mo.	F	SpLD1+2+3	Absent	BL temporoparietal	BL temporoparietal
2	11 yrs. 9 mo.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
3	14 yrs. 1 mo.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
4	9 yrs. 9 mo.	F	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
5	12 yrs. 9 mo.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
6	14 yrs. 11 mo.	F	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
7	15 yrs.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
8	11 yrs. 4 mo.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal
9	14 yrs. 7 mo.	M	SpLD1+2+3	ADHD	BL temporoparietal	BL temporoparietal

SpLD=specific learning disability; SpLD1=dyslexia; SpLD2=dysgraphia; SpLD3=dyscalculia; BL=bilateral; ADHD=attention deficit/hyperactivity disorder

Table 1b

Objective assessment using NeuroGam software of cerebral cortex perfusion pattern at rest (“baseline scan”) and after activation (“test scan”) in the study sample

Patient no.		Frontal lobe-L		Frontal lobe-R		Occipital lobe-L		Occipital lobe-R		Parietal lobe-L		Parietal lobe-R		Temporal lobe-L		Temporal lobe-R
		Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD
1	Baseline	73.1	11.7	73	11.3	72	9.7	74	12	72.1	7	74.3	6.7	65.5	12	67	11
	Test	73.3	12.2	75	11.9	72	11.4	77	14	74.3	7.9	76.9	6.8	64.9	12	70.2	13
	Delta	0.2	4.1	1.9	4.1	0.1	4.7	2.5	6	1.8	5	2.2	4.3	-0.4	4.6	2.6	5.6
2	Baseline	73.2	11.1	73	11.5	70.8	13.3	73.5	15	73.4	10.4	70.8	12.3	73	11.6	75	11.2
	Test	73.5	14.4	72.6	14.5	71.9	16.4	76.4	14.3	72.1	11.9	72.6	13.4	75.2	12.4	77.1	12.7
	Delta	0.2	6.8	-0.3	5.3	0.9	7	2.4	5.3	-1	4.8	1.5	5.2	1.8	5.4	1.8	4.7
3	Baseline	76.7	15.9	78	13.6	81.1	8.3	74.1	11.9	80.2	7.1	80.5	6.6	73.3	10.4	74.2	11.2
	Test	69.7	20.5	74.2	17.8	81.6	6.3	76.2	10.4	81.3	8.5	80.4	7.8	77.1	8.8	75	9.8
	Delta	-5.7	8	-3.2	7	0.4	3.5	1.8	4.2	0.9	3.3	-0.1	4	3.1	5.4	0.7	4.5
4	Baseline	69	14.9	70.4	15.2	70.9	8.2	67.7	13.5	69.2	12.1	74.4	10	70.4	11	70.7	10.8
	Test	73.3	13.9	75.6	14.9	73	9.6	70.9	13.6	71.7	13.1	77.7	9.7	74.8	10.6	74.8	10.5
	Delta	3.5	3.9	4.3	3.5	2.6	4	2.6	4	2.1	5	2.8	3.5	3.6	3.6	3.4	2.9
5	Baseline	67.8	11.8	68.1	11.3	72.9	10.2	66.6	17	71.3	8.7	70.9	9.5	63.2	11.6	65	11.1
	Test	67.1	12.1	69.4	12.4	76	8.4	71.8	13.5	72.9	8.9	70.4	10.7	68.3	10.3	69.6	9.7
	Delta	-0.6	7.1	1	7.2	2.5	4.7	4.3	6.2	1.3	4.3	-0.4	5.5	4.2	4.4	3.9	3.9
6	Baseline	72.5	12.4	75.4	10.6	78.7	10.2	80.3	12.5	80	8.4	80	6.9	71.3	13.3	72.6	12.8
	Test	74.9	12	78.3	10.8	77.8	11.1	79.9	12.5	82.9	8.3	83.5	6.9	71.2	13.3	72.3	11.6
	Delta	2	3	2.4	3.4	-0.7	3.6	-0.4	4.7	2.4	3.5	2.9	3.1	-1	3.1	-0.2	3.8
7	Baseline	66.6	13.6	71.6	12.3	72.8	12.5	77.2	10.8	70.7	10.1	69.8	9.6	62.3	13.4	66.5	11.6
	Test	60.6	16.7	71.2	11.7	70.6	13.2	76.4	11.0	69.6	9.9	71.9	8.7	60.3	15.4	66.1	12.7
	Delta	-5	6.6	-0.3	4.1	-1.8	3	-0.7	3.5	-0.9	2.7	1.8	3.8	-1.7	4	-0.3	4.1
8	Baseline	73.5	13	72.8	13.2	70.1	11.5	72.9	11.8	73.7	10.4	69.8	11.2	67.2	11.8	68.4	13.1
	Test	75.2	10.5	75	11.8	71	10.3	74.9	11	74.1	9.5	74.2	10.2	70	10.9	66.6	12.3
	Delta	1.4	4.8	1.9	4.2	0.8	3.5	1.7	3.8	0.3	4.8	3.6	4.2	2.3	4.7	-1.5	4.8
9	Baseline	70.5	13.6	75.6	14	76.4	11.1	69.4	14.2	78.9	7.3	76.4	10.7	68.1	10.1	67.1	9.3
	Test	67.5	15.8	75	15.9	77.7	15.1	75.9	13.5	80.3	7.6	74.2	11.6	73.5	8.8	73.7	8.8
	Delta	-2.5	5.9	-0.5	4.8	1.1	7.8	5.4	5.4	1.2	4.5	-1.8	6	4.5	4.7	5.4	5

R=right; L=left; SD=standard deviation

Discussion

In the present pilot study, comprising a small series of students having newly diagnosed SpLD, visual analysis showed reduction in regional blood flow both in “baseline scans“ and “test scans“ in temporoparietal areas. However, on quantitative assessment statistically significant difference in cerebral perfusion could not be identified. To our knowledge, only one study by Arduini et al. from Brazil[12] has reported brain SPECT scans in students with dyslexia. In their series of 34 students, they have done brain SPECT scans at rest and reported hypoperfusion on visual analysis in areas involved in reading and writing processes, namely, 80% had hypoperfusion in the temporal lobe, 20% had occipital hypoperfusion, and 10% had hypoperfusion in the frontal, parietal lobes, and cerebellum, respectively. Although our sample size is smaller, we have for the first time attempted quantitative assessment of brain perfusion in such students not only at rest but also after activating areas of learning.

In this study, all nine students had been referred for complaints of persistent difficulties in learning to effectively read, write, and do mathematical calculations, and assessment had revealed a primary diagnosis of SpLD. Comorbid ADHD was a secondary diagnosis in 8 of 9 (89%) of the study sample. In our study, visual analysis showed reduction in regional blood flow both in “baseline scans“ and “test scans“ in temporoparietal areas in all nine students. SPECT studies have reported that children with ADHD may show reduced perfusion in orbitofrontal, parietal, and cerebellar regions.[1314] Both SpLD and ADHD are common neurodevelopmental disorders and are well known to impair educational achievement and/or social functioning. However, students with SpLD + ADHD have more severe learning problems than those who have SpLD but no ADHD, and also more severe attention problems than those who have ADHD but no SpLD.[15] This could have been the reason for parents of students with SpLD + ADHD to consent to enlist them for the study. Some researchers have opined that the term comorbidity is of questionable value as the frequent co-occurrence of SpLD and ADHD is the result of a generalized atypical brain development, and overlap of neurodevelopmental disorders is the rule rather than exception.[1617]

Conclusion

Conducting a similar study in a larger number of students with SpLD (with and without ADHD) may help identify areas of cerebral cortex having significant hypoperfusion indicating decreased neuronal activity. Brain SPECT scan is noninvasive, involves minimal radiation,[18] and may serve as a robust tool to unravel etiopathogenesis of this invisible handicap.

Source of support

The Learning Disability Clinic at Seth G.S. Medical College & K.E.M. Hospital is partially funded by a research grant from Tata Interactive Systems, Mumbai.

Conflict of interest

Sunil Karande is the Editor of the Journal of Postgraduate Medicine.