Neurocircuitry of emotion and cognition in alcoholism: contributions from white matter fiber tractography

Dialogues Clin Neurosci. 2010;12(4):554-560.

Chronic alcoholism is characterized by impaired control over emotionally motivated actions towards alcohol use. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The extent to which cortical damage itself or cortical disconnection by white matter fiber pathway disruption contribute to deficits in emotion, cognition, and behavior can be investigated with in vivo structural neuroimaging and diffusion tensor imaging (DTI)-based quantitative fiber tracking. Tractography in alcoholism has revealed abnormalities in selective white matter fiber bundles involving limbic fiber tracts (fornix and cingulum) that connect cortico-limbic-striatal nodes of emotion and reward circuits. Studies documenting brain-behavior relationships support the role of alcoholism-related white matter fiber degradation as a substrate of clinical impairment. An understanding of the role of cortico-limbic fiber degradation in emotional dysregulation in alcoholism is now emerging.

Author Affiliations: 
Neuroscience Program, SRI International, Menlo Park, California, USA (Tilman Schulte); Neuroscience Program, SRI International, Menlo Park, California, USA; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA (Eva M. Müller-Oehring, Adolf Pfefferbaum); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA (Edith V. Sullivan) 
Address for correspondence: 

Emotions influence behavior and decisions. They are vital in evaluating whether perceived information is harmless or dangerous, for making appropriate responses, and for making rational decisions. [1]-[3] The ability to regulate emotions is thus essential for controlling actions, and difficulty with emotion regulation is a key factor of alcoholism. [4] For example, alcoholics exhibit deficits in decoding emotional facial expressions [5]-[10] and in controlling impulsivity, and they exhibit behavioral disinhibition whether sober or drunk. [11],[12] Selective brain systems that engage the amygdala play a crucial role in a tendency to experience negative emotion and in promoting alcohol intake. [13]-[15] Patients with selective damage to the amygdala have shown impaired recognition of negative emotions, [16] such as fear [17]-[19] or disgust. [20],[21] Chronic alcohol consumption is associated with widespread brain structural compromise, marked by gray and white matter shrinkage and ventricular enlargement seen in animal studies, [22],[23] human neuroimaging studies, [24]-[27] and with postmortem examination. [28]-[29] The observed emotional deficits and evidence for brain compromise suggest that the structural neurocircuitry of emotion and cognitive control may be affected in chronic alcoholism.

Neurocircuitry of emotion and cognition

Since the first demonstration of specific brain sites involved in pleasure, [30] extensive animal research has identified striatal and midbrain areas and their dopaminergic and glutamatergic projections to other brain structures as key components that regulate the reward circuit (for reviews see refs 31,32). Researchers using neuroimaging techniques recently confirmed the basic anatomy and pathways of cortico-striatal reward (eg, refs 33,34) and cortico-limbic emotion circuits in humans (eg, refs 35-38). The limbic system, located on the medial surface of the cerebral hemispheres, includes the rostral anterior cingulate cortex, hippocampus, and amygdala. [36]-[39] The structures comprising the limbic system are controversial, and structures such as the hypothalamus, thalamus, basal ganglia, dentate gyrus, entorhinal, piriform, and orbitofrontal cortices have been considered to be part of the limbic system by some but not all investigators. The amygdala directly mediates aspects of emotional learning and facilitates memory operations in other regions, including the hippocampus and prefrontal cortex (Figure 1). For example, neural plasticity in the amygdala was associated with encoding of the emotional component of memories, [40] with mediating aspects of reward learning, and with facilitating memory operations in other limbic regions involving hippocampus and prefrontal cortex. [41],[42] Within this neurocircuitry, the medial prefrontal cortex appears to exhibit inhibitory control over emotion- and reward-processing regions to prevent spontaneous and inappropriate emotional responses. This concept was confirmed by functional neuroimaging studies showing inverse activity levels in the medial prefrontal cortex and the amygdala. [43]-[46] Thus, it is not a single brain region, but rather the interaction of various interconnected structures, that enables emotional control.

Figure 1. Top: The cortico (green)-limbic (orange, red) emotion system consists of several brain regions that include amygdala, hippocampus, parahippocampal gyrus, anterior cingulate, and dorsolateral prefrontal cortex. It is involved in emotion, memory, emotional learning, and motivation with prefrontal cortices employing attentional and executive control over emotionally motivated actions. The cortico (green)-striatal (blue, yellow) reward system involves mesolimbic and mesocortical pathways from the ventral tegmental area (VTA, midbrain) to the striatum, particularly the ventral striatum (nucleus accumbens). The ventral striatum is connected to the thalamus and receives input from orbitofrontal and anterior cingulate cortices. Cortico-limbic and cortico-striatal circuits are partially overlapping and closely interconnected. Among the brain fiber bundles compromised in chronic alcoholism are cingulate (red) and fornix (blue) fiber bundles of the imbic system, [27] corpus callosum fiber bundles connecting cortical sites in the two cerebral hemispheres, [69] and mesencephalic (yellow) fibers connecting the pons to the midbrain. [67] Bottom: Parasagittal functional anisotropy image of a 67-year-old healthy man with fiber tracking of the cingulate bundle (red) and the fornix (green) superimposed

Functional and structural connectivity in cortico-limbic-striatal circuits

To test the functional relevance of interconnected limbic system structures, Cohen et al [35] combined measures of DTI-based fiber tracking with functional magnetic resonance imaging (fMRI)-based connectivity in healthy subjects. Their results yielded two dissociable amygdalacentered brain networks: (i) an amygdala-lateral orbitofrontal cortex network involved in relearning following a rule -switch; and (ii) an amygdala-hippocampus network involved in reward-motivated learning. Support for a role of cortico-limbic-striatal brain networks in both emotion and reward processing in alcoholism comes from recent fMRI studies indicating blunted amygdala activation to socially relevant faces in alcoholics [47] and enhanced ventral striatal activation to alcohol-related stimuli. [48] Further evidence for an interaction of emotion and reward systems in alcoholism comes from an fMRI study showing that anxiety ratings predicted parahippocampal activation to emotionally negative images, but not when these images were presented together with alcohol stimuli, [49] suggesting that alcohol cues attenuated the brain's responsiveness to fearful emotions.

Compromise of anatomical connections may impair neural signal transmission between brain regions involved in emotion processing and attentional bias toward alcohol cues in alcoholics. [50] Using white matter fiber tractography to understand how impaired integrity of neuroanatomical structural connectivity in corticolimbic-striatal circuits affects emotions and reward learning can explain how the effect of chronic alcoholism on these brain systems can mediate emotion, cognition, and behavior. Conditions such as the persistent preoccupation with alcohol, [10],[51] the inability to learn from negative consequences, and the lack of control over drinking behavior [52],[53] can be studied.

DTI fiber tractography

DTI has enabled quantitative fiber tracking for in vivo noninvasive mapping of inter-regional white matter fiber connections and the segmentation of axonal tracts in normal [54]-[56] and degraded brain systems [57],[58] (for a review see ref 59). DTI permits examination of the integrity of the microstructure of cerebral white matter by measuring the orientational displacement and distribution of water molecules in vivo across tissue components. [60] Water diffusion modeled with DTI is represented mathematically by an ellipsoid on a voxel-by-voxel basis. In fibers with a homogeneous or linear structure such as healthy white matter, the ellipsoid is long and narrow and has a preferential orientation, presumed to indicate the course of white matter fiber tracts. As such, DTIbased fiber tracking represents an indirect in vivo measure of neuronal pathways in the brain. DTI metrics include fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) or mean diffusivity (MD), which can be decomposed into two components, the longitudinal or axial diffusivity (Xl) and transverse or radial diffusivity (lt). High axial diffusivity is taken as an index of degradation of axonal health or integrity and radial diffusivity indexes the fibers' myelin sheath integrity. [61]-[63] This information can be used to determine which fiber tracts are and are not affected by chronic alcohol consumption; whether fiber compromise is due to axonal damage, a breakdown of the myelin sheath, or both; and how fiber microstructural integrity may relate to brain functional compromise. [64]-[66]

DTI-based quantitative fiber tracking in alcoholism

Until recently, few studies had investigated alcohol effects on microstructural integrity of fiber tracts by using DTI-based quantitative fiber tractography (chronic alcoholism [27],[67]-[69] ; fetal alcohol spectrum disorder7071; for review see ref 72). In our laboratory, we tracked 11 major white matter fiber bundles in 87 alcoholic and 88 control men and women. [27] Alcoholics demonstrated the greatest abnormalities in frontal, ie, frontal forceps, internal and external capsules, and more superior bundles, ie, fornix, superior cingulum, and superior longitudinal fasciculus, whereas posterior and inferior fibers were relatively spared. Tracking corpus callosum fibers, we found stronger alcohol effects for FA and radial than axial diffusivity, suggesting alcohol-related myelin degradation consistent with previously reported alcoholism-related neuropathology that included demyelination and loss of myelinated fibers. [28] Structure-function relationships between poorer performances on cognitive tests and DTI signs of regional white matter compromise in several fibers indicated that fiber degradation in alcoholism affects cognitive functions, and specifically cognitive processing speed. [27],[69] The role of alcoholism-related fiber degradation as a substrate of cognitive and also motor impairment was further supported by a double dissociation between functions and neuroanatomically defined callosal fiber bundles. In particular, prefrontal and temporal callosal fiber bundle integrity predicted psychomotor speed in a working memory task but not the ability to balance on one foot with eyes closed, and parietal fiber bundle integrity selectively predicted balance performance but not psychomotor speed. [69]

Chanraud et al [67] used DTI to investigate the effects of chronic alcoholism on mesencephalic fibers connecting the midbrain to the thalamus and the midbrain to the pons in 20 alcoholic and 24 control men. Alcoholics had fewer fibers than controls for midbrain-pons bundles but not for midbrain-thalamus bundles. The midbrainpons fiber deficit in alcoholics was predictive of poorer cognitive flexibility. This relation is consistent with the idea that cognitive functions and abilities are both mediated and constrained by the anatomical characteristics of the underlying white matter tracts interconnecting gray matter nodes of complex cortico-subcortical circuits, [73] and that disruption of selective (eg, mesencephalic) fiber bundles impairs cognition, such as mental flexibility.

Among the fiber tracts showing alcoholism-related microstructural compromise are the fornix and the cingulum, [27] two major fiber tracts of the limbic system. The fornix connects the hippocampus with hypothalamic regions including the mammillary bodies, and is involved in memory formation. [74]-[76] The cingulate bundle of the limbic system has long and short fibers that surround the corpus callosum and course along cingulate cortex and parahippocampal gyrus. The cingulate bundle connects orbitofrontal, dorsolateral prefrontal, and medial frontal cortices with parietal, temporal association, and medial temporal cortices including hippocampus and amygdala. The cingulum has been associated with several brain functions including pain and emotion, [77] cognitive and motor control, [25] memory, [78] and spatial orientation. [79],[80] Whether the degradation of fornix and cingulate fibers connecting cortico-limbic-striatal nodes of emotion and reward circuits is directly and selectively related to deficits in component processes of emotional regulation, cognitive control, reward learning, and the urge to drink in alcoholism remains to be investigated. Neuroimaging studies in alcoholism are beginning to link craving and binge drinking to cortico-limbic structural and functional integrity. [81]-[85]


recent advance of neuroimaging techniques such as DTI and fMRI have provided the opportunity to study structural and functional compromise of brain networks in chronic alcoholism. These studies provide clear evidence for brain-behavior relationships that support the role of alcoholism-related white matter fiber degradation as a substrate of cognitive and motor impairment. [27],[67]-[69] There is, however, limited understanding of the role of cortico-limbic fiber degradation on emotional dysfunction and impaired cognitive control of emotionally motivated actions in alcoholism. Thus, fiber tractography together with functional neuroimaging is an ideal combination to explore the role of regional cortico-limbic-striatal connectivity in emotion and cognition and their dysregulation in alcoholism.

1. Adolphs R, Tranel D, Damasio AR The human amygdala in social judgment. Nature. 1998;393:470-474 [ Pub Med ]
2. Damasio AR Emotion in the perspective of an integrated nervous system Brain Res Brain Res Rev. 1998;26:83-86 [ Pub Med ]
3. Lambie JA, Marcel AJ Consciousness and the varieties of emotion experience: a theoretical framework Psychol Rev. 2002;109:219-259 [ Pub Med ]
4. Fox HC, Hong KA, Sinha R Difficulties in emotion regulation and impulse control in recently abstinent alcoholics compared with social drinkers Addict Behav. 2008;33:388-394 [ Pub Med ]
5. Clark US, Oscar-Berman M, Shagrin B, Pencina M Alcoholism and judgments of affective stimuli Neuropsychology. 2007;21:346-362 [ Pub Med ]
6. Foisy ML, Kornreich C, Fobe A, et al. Impaired emotional facial expression recognition in alcohol dependence: do these deficits persist with midterm abstinence? Alcohol Clin Exp Res. 2007;31:404-410 [ Pub Med ]
7. Montagne B, Kessels RP, Wester AJ, de Haan EH Processing of emotional facial expressions in Korsakoff's syndrome Cortex. 2006;42:705-710 [ Pub Med ]
8. Oscar-Berman M, Hancock M, Mildworf B, Hutner N, Weber DA Emotional perception and memory in alcoholism and aging. Alcohol Clin Exp Res. 1990;14:383-393 [ Pub Med ]
9. Salloum JB, Ramchandani VA, Bodurka J, et al. Blunted rostral anterior cingulate response during a simplified decoding task of negative emotional facial expressions in alcoholic patients Alcohol Clin Exp Res. 2007;31:1490-1504 [ Pub Med ]
10. Townshend JM, Duka T Mixed emotions: alcoholics' impairments in the recognition of specific emotional facial expressions Neuropsychologia. 2003;41:773-782 [ Pub Med ]
11. Colder CR, O'Connor R Attention biases and disinhibited behavior as predictors of alcohol use and enhancement reasons for drinking Psychol Addict Behav. 2002;16:325-332 [ Pub Med ]
12. Dougherty DM, Marsh DM, Moeller FG, Chokshi RV, Rosen VC Effects of moderate and high doses of alcohol on attention, impulsivity, discriminability, and response bias in immediate and delayed memory task performance. Alcohol Clin Exp Res. 2000;24:1702-1711 [ Pub Med ]
13. Glahn DC, Lovallo WR, Fox PT Reduced amygdala activation in young adults at high risk of alcoholism: studies from the Oklahoma family health patterns project Biol Psychiatry. 2007;61:1306-1309 [ Pub Med ]
14. Heilig M, Koob GF A key role for corticotropin-releasing factor in alcohol dependence Trends Neurosci. 2007;30:399-406 [ Pub Med ]
15. Heinz A, Wrase J, Kahnt T, et al. Brain activation elicited by affectively positive stimuli is associated with a lower risk of relapse in detoxified alcoholic subjects Alcohol Clin Exp Res. 2007;31:1138-1147 [ Pub Med ]
16. Starkstein SE, Federoff JP, Price TR, Leiguarda RC, Robinson RG Neuropsychological and neuroradiologic correlates of emotional prosody comprehension Neurology. 1994;44(3 Pt 1):515-522 [ Pub Med ]
17. Adolphs R, Tranel D, Damasio H, Damasio A Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala Nature. 1994;372:669-672 [ Pub Med ]
18. Adolphs R, Tranel D, Damasio H, Damasio AR Fear and the human amygdala. J Neurosci. 1995;15:5879-5891 [ Pub Med ]
19. Anderson AK, Phelps EA Expression without recognition: contributions of the human amygdala to emotional communication Psychol Sci. 2000;11:106-111 [ Pub Med ]
20. Buchanan TW, Tranel D, Adolphs R Anteromedial temporal lobe damage blocks startle modulation by fear and disgust Behav Neurosci. 2004;118:429-437 [ Pub Med ]
21. Sprengelmeyer R The neurology of disgust Brain. 2007;130(Pt 7):1715-1717 [ Pub Med ]
22. Crews FT, Braun CJ, Hoplight B, Switzer RC, 3rd , Knapp DJ Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats Alcohol Clin Exp Res. 2000;24:1712-1723 [ Pub Med ]
23. Zou JY, Martinez DB, Neafsey EJ, Collins MA Binge ethanol-induced brain damage in rats: effect of inhibitors of nitric oxide synthase Alcohol Clin Exp Res. 1996;20:1406-1411 [ Pub Med ]
24. Harris GJ, Jaffin SK, Hodge SM, et al. Frontal white matter and cingulum diffusion tensor imaging deficits in alcoholism Alcohol Clin Exp Res. 2008;32:1001-1013 [ Pub Med ]
25. Makris N, Oscar-Berman M, Jaffin SK, et al. Decreased volume of the brain reward system in alcoholism. Biol Psychiatry. 2008;64:192-202 [ Pub Med ]
26. Pfefferbaum A, Adalsteinsson E, Sullivan EV Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women Biol Psychiatry. 2006;59:364-372 [ Pub Med ]
27. Pfefferbaum A, Rosenbloom M, Rohlfing T, Sullivan EV Degradation of association and projection white matter systems in alcoholism detected with quantitative fiber tracking Biol Psychiatry. 2009;65:680-690 [ Pub Med ]
28. Harper C, Dixon G, Sheedy D, Garrick T Neuropathological alterations in alcoholic brains. Studies arising from the New South Wales Tissue Resource Centre Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:951-961 [ Pub Med ]
29. Lewohl JM, Wixey J, Harper CG, Dodd PR Expression of MBP, PLP, MAG, CNP, and GFAP in the human alcoholic brain Alcohol Clin Exp Res. 2005;29:1698-1705 [ Pub Med ]
30. Olds J, Milner P Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain J Comp Physiol Psychol. 1954;47:419-427 [ Pub Med ]
31. Haber SN, Knutson B The reward circuit: linking primate anatomy and human imaging Neuropsychopharmacology. 2010;35:4-26 [ Pub Med ]
32. Zahr NM, Sullivan EV Translational studies of alcoholism: bridging the gap. Alcohol Res Health. 2008;31:215-230 [ Pub Med ]
33. Draganski B, Kherif F, Kloppel S, et al. Evidence for segregated and integrative connectivity patterns in the human basal ganglia J Neurosci. 2008;28:7143-152 [ Pub Med ]
34. Leh SE, Ptito A, Chakravarty MM, Strafella AP Fronto-striatal connections in the human brain: a probabilistic diffusion tractography study Neurosci Lett. 2007;419:113-118 [ Pub Med ]
35. Cohen MX, Elger CE, Weber B Amygdala tractography predicts functional connectivity and learning during feedback-guided decision-making. Neuroimage. 2008;39:1396-1407 [ Pub Med ]
36. Concha L, Gross DW, Beaulieu C Diffusion tensor tractography of the limbic system AJNR Am J Neuroradiol. 2005;26:2267-2274 [ Pub Med ]
37. Mark LP, Daniels DL, Naidich TP, Borne JA Limbic system anatomy: an overview AJNR Am J Neuroradiol. 1993;14:349-352 [ Pub Med ]
38. Smith KS, Tindell AJ, Aldridge JW, Berridge KC Ventral pallidum roles in reward and motivation Behav Brain Res. 2009;196:155-167 [ Pub Med ]
39. Benes FM Amygdalocortical circuitry in schizophrenia: from circuits to molecules Neuropsychopharmacology. 2010;35:239-257 [ Pub Med ]
40. Fanselow MS, Gale GD The amygdala, fear, and memory Ann N Y Acad Sci. 2003;985:125-134 [ Pub Med ]
41. Kelley AE Memory and addiction: shared neural circuitry and molecular mechanisms Neuron. 2004;44:161-179 [ Pub Med ]
42. LaBar KS, Cabeza R Cognitive neuroscience of emotional memory. Nat Rev Neurosci. 2006;7:54-64 [ Pub Med ]
43. Garcia R, Vouimba RM, Baudry M, Thompson RF The amygdala modulates prefrontal cortex activity relative to conditioned fear Nature. 1999;402:294-296 [ Pub Med ]
44. Kim H, Somerville LH, Johnstone T, Alexander AL, Whalen PJ Inverse amygdala and medial prefrontal cortex responses to surprised faces Neuroreport. 2003;14:2317-2322 [ Pub Med ]
45. Quirk GJ, Likhtik E, Pelletier JG, Pare D Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons J Neurosci. 2003;23:8800-8807 [ Pub Med ]
46. Shin LM, Wright CI, Cannistraro PA, et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder Arch Gen Psychiatry. 2005;62:273-281 [ Pub Med ]
47. Marinkovic K, Oscar-Berman M, Urban T, et al. Alcoholism and dampened temporal limbic activation to emotional faces. Alcohol Clin Exp Res. 2009;33:1880-1892 [ Pub Med ]
48. Wrase J, Schlagenhauf F, Kienast T, et al. Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics Neuroimage. 2007;35:787-794 [ Pub Med ]
49. Gilman JM, Hommer DW Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients Addict Biol. 2008;13:423-434 [ Pub Med ]
50. Noel X, Van der Linden M, d'Acremont M, et al. Alcohol cues increase cognitive impulsivity in individuals with alcoholism Psychopharmacology (Berl). 2007;192:291-298 [ Pub Med ]
51. Roberts AJ, Koob GF The neurobiology of addiction: an overview. Alcohol Health Res World. 1997;21:101-106 [ Pub Med ]
52. Lyvers M "Loss of control" in alcoholism and drug addiction: a neuroscientific interpretation Exp Clin Psychopharmacol. 2000;8:225-249 [ Pub Med ]
53. Skutle A, Berg G Training in controlled drinking for early-stage problem drinkers Br J Addict. 1987;82:493-501 [ Pub Med ]
54. Bodammer NC, Kaufmann J, Kanowski M, Tempelmann C Monte Carlobased diffusion tensor tractography with a geometrically corrected voxelcentre connecting method Phys Med Biol. 2009;54:1009-1033 [ Pub Med ]
55. Kamali A, Kramer LA, Hasan KM Feasibility of prefronto-caudate pathway tractography using high resolution diffusion tensor tractography data at 3T J Neurosci Methods. 2010;191:249-254 [ Pub Med ]
56. Mori S, Wakana S, Nagae-Poetscher LM, van Zijl PCM M RI Atlas of Human White Matter. 2005;XX:XX-XX [ Pub Med ]
57. Kleiser R, Staempfli P, Valavanis A, Boesiger P, Kollias S Impact of fMRIguided advanced DTI fiber tracking techniques on their clinical applications in patients with brain tumors Neuroradiology. 2010;52:37-46 [ Pub Med ]
58. Lowe MJ, Horenstein C, Hirsch JG, et al. Functional pathway-defined MRI diffusion measures reveal increased transverse diffusivity of water in multiple sclerosis Neuroimage. 2006;32:1127-1133 [ Pub Med ]
59. Sullivan EV, Pfefferbaum A Diffusion tensor imaging in aging and agerelated neurodegenerative disorders In: Jones DK, ed Diffusion MRI: Theory, Methods, and Applications. 2010:624-643
60. Basser PJ, Pierpaoli C A simplified method to measure the diffusion tensor from seven MR images Magn Reson Med. 1998;39:928-934 [ Pub Med ]
61. Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002;17:1429-1436 [ Pub Med ]
62. Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain Neuroimage. 2005;26:132-140 [ Pub Med ]
63. Sun SW, Liang HF, Trinkaus K, Cross AH, Armstrong RC, Song SK Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magn Reson Med. 2006;55: 302-308 [ Pub Med ]
64. Aralasmak A, Ulmer JL, Kocak M, Salvan CV, Hillis AE, Yousem DM Association, commissural, and projection pathways and their functional deficit reported in literature J Comput Assist Tomogr. 2006;30:695-715 [ Pub Med ]
65. Kobayashi T, Oida T An MR-DTI-based fiber tracking method for the multimodal integrative study of cognitive brain functions Conf Proc IEEE Eng Med Biol Soc. 2008;2008:5498-5501 [ Pub Med ]
66. Yamada K, Ito H, Nakamura H, et al. Stroke patients' evolving symptoms assessed by tractography. J Magn Reson Imaging. 2004;20:923-929 [ Pub Med ]
67. Chanraud S, Reynaud M, Wessa M, et al. Diffusion tensor tractography in mesencephalic bundles: relation to mental flexibility in detoxified alcohol-dependent subjects Neuropsychopharmacology. 2009;34:1223-1232 [ Pub Med ]
68. Rosenbloom MJ, Sassoon SA, Fama R, Sullivan EV, Pfefferbaum A Frontal callosal fiber integrity selectively predicts coordinated psychomotor performance in chronic alcoholism Brain Imaging Behav. 2008;2:74-83 [ Pub Med ]
69. Pfefferbaum A, Rosenbloom MJ, Fama R, Sassoon SA, Sullivan EV Transcallosal white matter degradation detected with quantitative fiber tracking in alcoholic men and women: selective relations to dissociable functions Alcohol Clin Exp Res. 2010;34:1201-1211 [ Pub Med ]
70. Lebel C, Rasmussen C, Wyper K, Andrew G, Beaulieu C Brain microstructure is related to math ability in children with fetal alcohol spectrum disorder Alcohol Clin Exp Res. 2010;34:354-363 [ Pub Med ]
71. Lebel C, Rasmussen C, Wyper K, et al. Brain diffusion abnormalities in children with fetal alcohol spectrum disorder Alcohol Clin Exp Res. 2008;32:1732-1740 [ Pub Med ]
72. Chanraud S, Zahr N, Sullivan EV, Pfefferbaum A MR diffusion tensor imaging: a window into white matter integrity of the working brain Neuropsychol Rev. 2010;20:209-225 [ Pub Med ]
73. Toosy AT, Ciccarelli O, Parker GJ, Wheeler-Kingshott CA, Miller DH, Thompson AJ Characterizing function-structure relationships in the human visual system with functional MRI and diffusion tensor imaging Neuroimage. 2004;21:1452-1463 [ Pub Med ]
74. Aggleton JP, Neave N, Nagle S, Sahgal. A A comparison of the effects of medial prefrontal, cingulate cortex, and cingulum bundle lesions on tests of spatial memory: evidence of a double dissociation between frontal and cingulum bundle contributions J Neurosci. 1995;15:7270-7281 [ Pub Med ]
75. Sziklas V, Petrides M Memory and the region of the mammillary bodies Prog Neurobiol. 1998;54:55-70 [ Pub Med ]
76. Vann SD, Aggleton JP The mammillary bodies: two memory systems in one? Nat Rev Neurosci. 2004;5:35-44 [ Pub Med ]
77. Vogt BA Pain and emotion interactions in subregions of the cingulate gyrus Nat Rev Neurosci. 2005;6:533-544 [ Pub Med ]
78. Charlton RA, Barrick TR, Lawes IN, Markus HS, Morris RG White matter pathways associated with working memory in normal aging Cortex. 2010;46:474-489 [ Pub Med ]
79. Harker KT, Whishaw IQ Impaired place navigation in place and matching-to-place swimming pool tasks follows both retrosplenial cortex lesions and cingulum bundle lesions in rats Hippocampus. 2004;14:224-231 [ Pub Med ]
80. Warburton EC, Aggleton JP, Muir JL Comparing the effects of selective cingulate cortex lesions and cingulum bundle lesions on water maze performance by rats Eur J Neurosci. 1998;10:622-634 [ Pub Med ]
81. Myrick H, Anton RF, Li X, et al. Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving Neuropsychopharmacology. 2004;29:393-402 [ Pub Med ]
82. Schneider F, Habel U, Wagner M, et al. Subcortical correlates of craving in recently abstinent alcoholic patients Am J Psychiatry. 2001;158:1075-1083 [ Pub Med ]
83. Sinha R, Li CS Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications Drug Alcohol Rev. 2007;26:25-31 [ Pub Med ]
84. Tapert SF, Brown GG, Baratta MV, Brown SA fMRI BOLD response to alcohol stimuli in alcohol dependent young women Addict Behav. 2004;29:33-50 [ Pub Med ]
85. Tapert SF, Cheung EH, Brown GG, et al. Neural response to alcohol stimuli in adolescents with alcohol use disorder Arch Gen Psychiatry. 2003;60:727-735 [ Pub Med ]