White matter alterations in anorexia nervosa: A systematic review of diffusion tensor imaging studies

Table 1 Baseline characteristics of the included studies (all cross-sectional in design)

Ref.	AN subtype	ED subtype	Study purpose	Method DTI	Assessment
Kazlouski et al[13]	Current AN restricting and purging subtype	AN purging and restricting subtype	Test of the brain WM integrity alteration and its relation to heightened anxiety in AN	GE 3 Tesla whole-body MRI scanner, maximum gradient amplitude of 40 Mt/M and maximum slew rate of 150 T/m per second, 8-channel phased-array head coil	SCID-CV
					EDI-3
					TCI
					STAI
					BDI
Frank et al[49]	Current AN restricting and purging subtype	AN	Analysis of GM and WM in a sample of adolescents in comparison to adults	Signa 3T Scanner, axial, 3-dimensional, T-1 weighted magnetization-prepared rapid acquisition gradient echo	C-DISC
					EDI-3
					TCI
					STAI
					CDI
					SPSRQ
					9 point Likert scale sweetness-pleasantness of 1 molar sucrose
Nagahara et al[7]	Current AN, NS subtype	AN	Exploration of WM abnormalities in AN patients compared to HC	Whole body 3 Tesla MR system with an eight-channel phased-array head coil	SCID-CV
					EDI-2
					BDI-II
Via et al[53]	Current AN restricting subtype	AN	Assessment of WM microstructure in a clinical sample of AN patients	GE Signa Excite scanner at 1.5 T equipped with an 8-channel phased-array head coil	SCID-CV
					SCID-I/NP
					GHQ-28
					EDI-2
					HAM-D
					HAM-A
Frieling et al[5]	Current AN with NS subtype and recovered women from AN	AN and recovered women from AN	Assessment of the microstructural integrity of WM pathways through DTI in women with AN	3 T Siemens-scanner, with a gradient field strength up to 45 MT/m	None
Yau et al[39]	Recovered women from restricting type AN	Recovered women from restricting type AN	Examination of the microstructural alterations of WM integrity in recovered AN women	3.0 Tesla Discovery MR750 scanner with an 8-channel phase-array head coil	SCID-CV
					MINI
					TCI
					STAI
					MPS

AN: Anorexia nervosa; DTI: Diffusion tensor imaging; GM: Gray matter; HC: Healthy controls; NS: Non-specified; WM: White matter.

Table 2 Characteristics of the participant samples in the reported studies

Ref.	AN subtype	Total size	Sample characteristics
			n
			Gender
			Mean ± SD:
			Age/years
			BMI
			Duration of illness/years
			ED group (AN)	Recovered AN	Healthy group
Kazlouski et al[13]	Current AN restricting and purging subtype	n = 33	n = 16 (10 resAN, 6 purgAN)	-	n = 17
			Female		Female
			23.9 ± 7 SD		25.1 ±4 SD
			16.5 ± 1 SD		21.5 ±1 SD
			7.5 ± 8 SD		NA
Frank et al[49]	Current AN restricting and purging subtype	n = 41	n = 19 (17 resAN, 2 purgAN)	-	n =22
			NS		Female
			15.4 ± 1.4 SD		14.8 ± 1.8 SD
			16.2 ± 1.1 SD		21.3 ± 1.9 SD
			NS		NA
Nagahara et al[7]	Current AN, NS subtype	n = 35	n = 17	-	n = 18
			Female		Female
			23.8 ± 6.68 SD		26.2 ± 5.6 SD
			13.6 ± 1.3 SD		19.9 ± 2.0 SD
			4.93 ± 4.9 SD		NA
Via et al[53]	Current AN restricting subtype	n = 38	n = 19	-	n = 19
			Female		Female
			28.37 ± 9.55 SD		28.63 ± 8.58 SD
			17.03 ± 1.09 SD		21.09 ± 1.80 SD
			6.52 ± 6.03 SD		NA
Frieling et al[5]	Current AN with NS subtype and recovered women from AN	n = 41	n = 12	n = 9	n = 20
			Female	Female	Female
			26.8 ± 6.94 SD	27.44 ± 5.3 SD	24.80 ± 2.6 SD
			15.18 ± 1.39 SD	19.31 ± 1.39 SD	19.60 ± 0.94 SD
			NS	NS	NA
Yau et al[39]	Recovered women from restricting type AN	n = 22	-	n = 12	n = 10
				Female	Female
				28.7 ± 7.9 SD	26.7 ± 5.4 SD
				21.2 ± 1.5 SD	22.0 ± 1.1. SD
				5.6 ± 5.2	NA

AN: Anorexia nervosa; recAN: Recovered anorexia nervosa; purgAN: Purgative subtype anorexia nervosa; resAN: Restrictive subtype anorexia nervosa; BMI: Body mass index; NA: Non-applicable; NS: Non-specified.

Table 3 Main diffusion tensor imaging outcomes and author interpretation

Ref.	AN subtype	Outcomes: DTI measures and areas in AN	Author interpretation
Kazlouski et al[13]	Current AN restricting and purging subtype	FA: Lower in the bilateral fimbria-fornix, fronto-occipital and cingulum fiber tracts	Anxiety is predicted by the fimbria-fornix FA value. Thus, reduced WM integrity could provide a mechanism for heightened anxiety
Frank et al[49]	Current AN restricting and purging subtype	FA: Lower in fornix, cingulum and corpus callosum (corona radiata and forceps mayor)	Abnormal fornix integrity could lead to altered feedback between limbic and higher-order brain structures. The corpus callosum could be implicated in taste processing
Nagahara et al[7]	Current AN, NS subtype	FA: Lower value in the left cerebellum	WM abnormalities in the fornix and the cerebellum may be neural substrates of the pathophysiology of AN. The fornix is one of the important components of the Papez circuit, which links the limbic system with other brain structures. The correlation of WM alteration with physical severity, including BMI and duration of illness may indicate that WM alteration is more relevant with regard to physical severity rather than psychological severity
		MD: Higher value in the fornix
Via et al[53]	Current AN restricting subtype	FA: Lower in the parietal part of the left SLF and the fornix.	The left SLF seem relevant to body image distortion as well as other cognitive processes like the called weak central coherence. The fornix is a key structure involved in the regulation of body-energy balance and processing of reward responses
		MD: Higher in the SLF and the fornix. They also reported significantly increased MD in the fornix, accompanied by decreased FA and increased RD and AD
Frieling et al[5]	Current AN with NS subtype and recovered women from AN	FA (AN and recAN): Lower in the posterior thalamic radiation bilaterally (which includes the of optic radiation) and the left mediodorsal thalamus	The posterior thalamic radiation fibres project to areas involved in the processing of the body image, whose alteration could explain the AN body image distortion. The left mediodorsal thalamic nucleus is connected to regions contributing to impairments in cognitive domains, especially set/shifting ability, executive control, habit learning and reward processing
Yau et al[39]	Recovered women from restricting type AN	FA (recAN): Insignificant alteration	Lower MD was associated with harm avoidance, suggesting a possible underlying trait associated with AN. Localization of disturbances in frontal-parietal and cingulum WM suggests that these pathways, which are important for cognitive control, may be susceptible to core AN pathology. Malnutrition seems to have potentially lasting effects on WM integrity and degree of recovery
		MD: Lower in frontal, parietal and cingulum

AD: Axial diffusivity; AN: Anorexia nervosa patients; HC: Healthy controls; FA: Fractional anisotropy; MD: Mean diffusivity; recAN: Recovered from AN; SLF: Superior longitudinal fasciculus; WM: White matter; RD: Radial diffusivity.

Table 4 Quality assessment of the retrieved studies

Ref.	Q1	Q2	Q3	Q5	Q6	Q15	Q18	Q25
	Hypothesis clearly described	Main outcomes clearly described in the introduction or methods section	Participants characteristics clearly described	Distributions of confounders in each group of subjects clearly described	Main study findings clearly described	Study measurement blind	Appropriateness of the statistical tests	Adjustment for confounding
Kazlouski et al[13]	Yes	Yes	Yes	No	Yes	U	U	No
Frank et al[49]	Yes	Yes	Yes	Partially	Yes	U	Yes	Yes
Nagahara et al[7]	Yes	Yes	Yes	No	Yes	U	Yes	No
Via et al[53]	Yes	Yes	Yes	Yes	Yes	U	Yes	Yes
Frieling et al[5]	Yes	Yes	Yes	Yes	Yes	U	Yes	Yes
Yau et al[39]	Yes	Yes	Yes	No	Yes	U	Yes	No

Q4 regarding to interventions of interest clearly described was not applicable to this review since any of the studies undertook an interventional design. Yes scored as 1, No scored as 0, Partially scored as 0.5. U: Unable to determine.