Table 3. DTI studies of relatives of bipolar disorders.

Authors	Sample	Mean age (years) ±SD	DTI method	Analysis method	Abnormalities in relatives compared to healthy controls	Additional modalities	Comments/limitations
Frazier et al., 2007	7 Relatives 8 HC 10 DSM-IV BD-I	8.9±3.0 9.2±2.4 9.2±3.0	1.5 T	ROI	Reduced FA in the bilateral SLF I	Clinical characteristics	The patients and the relatives weren't biologic relatives The participants were aged 4 to12 years old. HC had no history of DSM-IV axis I diagnosis HC had no family history of psychiatric disorders in first degree relatives Exclusion criteria for all groups were: learning disabilities, history of claustrophobia, autism, schizophrenia, anorexia or bulimia nervosa, alcohol and drug dependence/abuse (during2 months prior to scan, ortotal past history of more than12 months), history of ECT All of the relatives had ADHD and/or CODD and/or diagnosis of anxiety disorder One child in the relatives group was taking stimulant treatment Not indicated whether the proband of relatives had psychotic symptoms during affective episodes or type of bipolar disorder
Chaddock et al., 2009	21 Relatives 18 HC 19 DSM-IV BD-I	42.5±13.6 41.7±12.2 43.3±10.2	1.5 T	VBA	There were no significant FA differences	Genetic liability	All of the patients had experienced psychotic symptoms during episode of illness exacerbation Patients and relatives were biologically related Substance or alcohol dependence in the 12 months prior to assessment was the exclus(X00131)on criteria for all groups None of the relatives or HC had ever experienced a psychotic illness Four of the relatives fulfilled criteria for a non-psychotic Axis I disorder during their lifetime None of the relatives were taking psychotropic medication at the time of scanning In HC group, one participant fulfilled lifetime DSM-IV criteria for major depressive disorder, and one participant for alcohol misuse (both recovered) None of the HC had ever received psychotropic medication.
Versace et al., 2010	20 healthy offspring (BD) (HBO) 25 HC offspring (HC) (CONT)	13.2±2.5 13.9±2.6	3 T	TBSS	In the region of CC HBO had greater FA and decreased RD In the region of the right ILF in the temporal pole HBO had decreased RD In the region of the right ILF in the visual cortex HBO had greater AD	Age related analysis	Participants didn't endorse any current DSM-IV Axis I diagnosis or a history of depression or BD Parents of the HBO were diagnosed with BD-I, BD-II,BD NOS. Parents of the CONT didn't have any current Axis I disorder or history of mood disorder or psychotic disorder Participants in this study were aged 8 to 17 Not indicated whether the parents of the HBO had psychotic symptoms during affective episodes
Sprooten et al., 2011	117 Relatives 79 HC	21.0±2.8 20.8±2.3	1.5 T	VBA TBSS	VBA showed reduced FA in: The genu and parts of the splenium of the CC Internal and external capsules ILF SLF IFOF AF UF Parts of the CS tract Subcortical WM mainly in the parietal and frontal lobes TBSS showed reduced FA in: CC Internal and external capsules (including anterior thalamic radiations) ILF SLF IFOF UF Parts of the CS tract Subcortical WM around the central sulci	Cyclothymic temperament	Relatives had at least one first-degree or two second-degree relatives with BD-I (diagnosed with DSM-IV) No participant had an Axis I disorder To optimize matching on key confounds, control subjects were recruited from the social networks of the high risk subjects themselves Not indicated whether the proband of relatives had psychotic symptoms during affective episodes
Mahon et al., 2013	15 Siblings 27 HC 26 DSM-IV BD (I-II)	42.0±11.7 40.8±12.5 40.6±12.4	3 T	TBSS Probabilistic Tractography	TBSS showed reduced FA in the right temporal WM Probabilistic tractography indicated reduced FA along the right IFOF	Impulsivity measures	Some of the siblings were biologically related to patients in the study Patients were diagnosed with BD-I or BD-II (diagnosed with DSM-IV) Siblings and HC were free from current Axis I major mood or psychotic disorders Siblings were at least 25 years of age and were past the age of onset in their affected sibling One sibling met criteria for a single postpartum depressive episode that remitted without treatment, two other siblings met criteria for prior substance use disorders, and one of these siblings also met criteria for Anxiety Disorder NOS One sibling was being treated with a SSRI for anxiety; all other siblings and HC were free from psychotropic medication Not indicated whether the proband of relatives had psychotic symptoms during affective episodes
Linke et al., 2013	22 Relatives 22 HC	28±11 28±10	3 T	ROI	Reduced FA in: The right ALIC The right UF Increased RD in the right ALIC	Executive functions Correlations between FA values and executive functions	Relatives and HC had no Axis I or Axis II disorder HC had no mental disorder in their first degree relatives Eleven relatives were from simplex families (one case of BD-I in the family), there maining eleven were from multiplex families (two or more cases of BD-I in the family) Not indicated whether the proband of relatives had psychotic symptoms during affective episodes
Emsell et al., 2013	21 Relatives 18 HC 19 DSM-IV BD-I	42.5±13.6 41.7±12.2 43.3±10.2	1.5 T	Tractography	There were no significant FA or RD differences.	Genetic liability	This study is an extention of a previously published study(Chaddock et al, 2009) All of the patients had experienced psychotic symptoms during episode of illness exacerbation Patients and relatives were biologically related Substance or alcohol dependence in the 12 months prior to assessment was the exclusion criteria for all groups None of the relatives or HC had ever experienced a psychotic illness Four of the relatives fulfilled criteria for a non-psychotic Axis I disorder during their lifetime None of the relatives were taking psychotropic medication at the time of scanning In HC group, one participant fulfilled lifetime DSM-IV criteria for major depressive disorder, and one participant for alcohol misuse (both recovered) None of the HC had ever received psychotropic medication.
Sprooten et al., 2013	60 Siblings 46 HC 64 DSM-IV BD-I	30.4±12.5 30.1±10.6 31.7±11.4	3 T	TBSS ROI	TBSS indicated reduced FA in: Splenium/ body of CC Posterior tatamic radiations Posterior corona radiata Left SLF ROI didn't indicate significant differences	Correlations with clinical measures and potential confounds	Patients and relatives were biologically related Some of the patients had episodes with psychotic features Sibling were mostly past the typical age of BD onset Siblings were not excluded for anxiety disorders, a single episode of major depression, or past substance abuse or dependence HC subjects had no lifetime history of axis I psychiatric disorder or family history of mood or psychotic disorders Participants were excluded for alcohol or drug abuse or dependence within the past six months

HC, healthy controls; BD, bipolar disorder; BD NOS, bipolar disorder not other specified; HBO, healthy offspring with a parent diagnosed with bipolar disorder; CONT; healthy control offspring of healthy parents; ADHD, attention deficit hyperactivity disorder; CODD, conduct/oppositional defiant disorder; DTI, diffusion tensor imaging; ROI, region of interest; VBA, voxel based approach; TBSS, tract-based spatial statistics; FA, fractional anisotropy; RD, radial diffusivity; AD, axial diffusivity, WM, white matter; SLF, superior longitudinal fasciculus; CC, corpus callosum; ILF, inferior longitudinal fasciculus; IFOF, inferior fronto-occipital fasciculus; ALIC, anterior limb of internal capsule; AF, arcuate fasciculus; UF, uncinate fasiculus; CS, cortico-spinal; DSM-IV; Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; SSRI, selective serotonin reuptake inhibitor; ECT, electro-convulsive therapy.