BOLD Based MRI Functional Connectivity December 2, 2011

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1 BOLD Based MRI Functional Connectivity December 2, 2011 Luigi Maccotta, MD, PhD Adult Epilepsy Center Washington University School of Medicine American Epilepsy Society Annual Meeting

2 Support Disclosure 1. NIH NCRR: UL1 RR024992, Sub-Award KL2 RR NIH - Ruth L. Kirschstein Nat. Service Research Award: T32 NS Clinical Trials 1. Eisai: E2007-G Upshire Smith: P09-004, P Speakers Bureau: none Consultantship: none I own no stocks or equity in any pharmaceutical company 1.. American Epilepsy Society Annual Meeting 2

3 Learning Objectives 1. Outline typical semiologic features of a focal epileptic seizure 2. Identify brain regions typically involved in the pathology of TLE 3. Understand the concept of TLE as a network disease 4. Understand the role of functional MRI in characterizing network features of TLE and the potential role for targeted therapeutic interventions American Epilepsy Society Annual Meeting 3

4 Temporal lobe epilepsy as a network disease Is TLE a disease of networks? What does this mean? A disease process that affects a region connected to a network of brain regions, and as a result causes changes in the other regions in the network 4

5 Temporal lobe epilepsy as a network disease Is TLE a disease of networks? What does this mean? A disease process that affects a region connected to a network of brain regions, and as a result causes changes in the other regions in the network A disease process that changes the way different brain regions are connected, or whose main manifestation is a product of the change in the connections between brain regions 5

6 TLE: Semiologic features Focal epileptic seizures march across the brain in a specific sequence of activation, which determines the semiology: I think the mode of beginning makes a great difference as to the march of the fit. When the fit begins in the face, the convulsion in involving the arm may go down the limb When the fit begins in the leg, the convulsion marches up; when the leg is affected after the arm, the convulsion marches down the leg. Hughlings Jackson, J. Notes on the physiology and pathology of the nervous system, Med Times Gaz, 1868, ii:

7 TLE: Semiologic features Focal epileptic seizures march across the brain in a specific sequence of activation, which determines the semiology: I think the mode of beginning makes a great difference as to the march of the fit. When the fit begins in the face, the convulsion in involving the arm may go down the limb When the fit begins in the leg, the convulsion marches up; when the leg is affected after the arm, the convulsion marches down the leg. Hughlings Jackson, J. Notes on the physiology and pathology of the nervous system, Med Times Gaz, 1868, ii: 696. Examining the succession of symptoms and signs can help us localize which brain structures are involved by ictal activity and in what order 7

8 Focal seizures have a typical semiology Temporobasal/Limbic: Intact consciousness at onset, may have warning, slight confusion Nausea, cephalic aura Pupillary change, flush, pallor, warm feeling Malaise, fear, sadness Oroalimentary automatisms Unilateral or bilateral face, trunk tonic/clonic Déjà vu Behavioral arrest Wieser,

9 Specific semiology argues for a specific set of regions Sequential activation of specific brain structures suggests a preferred pathway of propagation (e.g. Jouny et al., 2007) 9

10 A seizure as propagation through a network Ictal Onset Zone 10

11 A seizure as propagation through a network Ictal Onset Zone 11

12 Seizure propagation is specific Ictal Onset Zone 12

13 The disease process could cause chronic changes Ictal Onset Zone 13

14 Remote regions indirectly connected could also be affected Ictal Onset Zone 14

15 Other regions may serve a compensatory role Ictal Onset Zone 15

16 Other regions may function as gatekeepers Ictal Onset Zone 16

17 An epilepsy network of increasing complexity? Ictal Onset Zone 17

18 Functional connectivity Functional MRI allows the study of brain function in a noninvasive fashion in human beings 18

19 Functional connectivity Functional MRI allows the study of brain function in a noninvasive fashion in human beings It tracks the level of blood oxygenation with good spatial resolution and fair temporal resolution 19

20 Functional connectivity Functional MRI allows the study of brain function in a noninvasive fashion in human beings It tracks the level of blood oxygenation with good spatial resolution and fair temporal resolution Functional connectivity refers to the practice of regressing fmri signal between two regions of the brain to determine how closely coupled they are: the closer the similarity between the two signals, the more the two regions are said to be functionally connected 20

21 Functional connectivity Functional MRI allows the study of brain function in a noninvasive fashion in human beings It tracks the level of blood oxygenation with good spatial resolution and fair temporal resolution Functional connectivity refers to the practice of regressing fmri signal between two regions of the brain to determine how closely coupled they are: the closer the similarity between the two signals, the more the two regions are said to be functionally connected Akin to: If they fire together, they are wired together 21

22 Functional connectivity 22

23 Functional connectivity SEED 23

24 Functional connectivity SEED + + t 24

25 Functional connectivity SEED + + t AVERAGE SEED TIME SERIES 25

26 Functional connectivity SEED + + t AVERAGE SEED TIME SERIES VOXELWISE REGRESSION 26

27 Functional connectivity SEED + + t AVERAGE SEED TIME SERIES VOXELWISE REGRESSION CORRELATION MAP 27

28 Functional connectivity in TLE There has been increasing interest in applying the methods of functional connectivity fmri (fcmri) to the study of epilepsy, with at times conflicting results 28

29 Functional connectivity in TLE There has been increasing interest in applying the methods of functional connectivity fmri (fcmri) to the study of epilepsy, with at times conflicting results A few groups have concluded that TLE can lead to decreases in functional connectivity of the medial temporal region (e.g. Bettus et al., 2008, 2009) 29

30 Functional connectivity in TLE There has been increasing interest in applying the methods of functional connectivity fmri (fcmri) to the study of epilepsy, with at times conflicting results A few groups have concluded that TLE can lead to decreases in functional connectivity of the medial temporal region (e.g. Bettus et al., 2008, 2009) Others have looked at whole-brain effects, in an attempt to characterize network properties, and in certain instances showed increased connectivity (Liao et al., 2010) 30

31 Functional connectivity in TLE Liao et al.,

32 Functional connectivity in primary generalized epilepsy Functional connectivity fmri has also been used to investigate idiopathic or primary generalized epilepsy 32

33 Functional connectivity in primary generalized epilepsy Functional connectivity fmri has also been used to investigate idiopathic or primary generalized epilepsy While some studies did not show changes in functional connectivity (Moeller et al., 2011) others primarily noted increased connectivity within thalamic, basal ganglia and motor networks, possibly reflecting the nature of the disease 33

34 Functional connectivity in primary generalized epilepsy Luo et al.,

35 Functional connectivity as a predictor of surgical success Negishi et al.,

36 Focus: regions involved in seizure propagation 36

37 Methods 32 patients with TLE (20 with left TLE, 12 with right TLE) consecutively enrolled through the Washington University Adult Epilepsy Center 37

38 Methods 32 patients with TLE (20 with left TLE, 12 with right TLE) consecutively enrolled through the Washington University Adult Epilepsy Center Confirmed unilateral medial temporal lobe epilepsy with video-eeg 38

39 Methods 32 patients with TLE (20 with left TLE, 12 with right TLE) consecutively enrolled through the Washington University Adult Epilepsy Center Confirmed unilateral medial temporal lobe epilepsy with video-eeg A subset of the patients had MRI evidence of medial temporal sclerosis and/or hippocampal atrophy 39

40 Methods 32 patients with TLE (20 with left TLE, 12 with right TLE) consecutively enrolled through the Washington University Adult Epilepsy Center Confirmed unilateral medial temporal lobe epilepsy with video-eeg A subset of the patients had MRI evidence of medial temporal sclerosis and/or hippocampal atrophy Patients with bitemporal or extratemporal seizures, developmental anomalies, or other unusual pathology were excluded 40

41 Methods A group of age, gender, and handedness-matched healthy control subjects (n = 32) acquired under identical imaging conditions was used for comparison 41

42 Methods A group of age, gender, and handedness-matched healthy control subjects (n = 32) acquired under identical imaging conditions was used for comparison Imaging Resting-state BOLD fmri session (2 BOLD runs, each approximately 6 minutes) 3 T scanner 42

43 Anatomically derived regions of interest (ROIs) HIPPO HEAD HIPPO BODY ENTO- RHINAL PARAHIPPO INSULA A priori ROIs serve role as seeds in functional connectivity and later as regions of interest in the ROI analysis of the connectivity data 43

44 Does the medial temporal region form a functional network in healthy subjects? 44

45 Strong coupling between healthy medial temporal regions Maccotta & Hogan,

46 Does TLE change the medial temporal functional network? 46

47 Effect of TLE: Difference maps p <.05 p < 10-6 I TLE C CTL TLE - CTL SEED Maccotta et al., 2011, in preparation 47

48 Medial temporal functional network in TLE I HIPPO HEAD C 48

49 TLE changes the medial temporal functional network p <.05 p < 10-4 I C SEED Maccotta et al., 2011, in preparation 49

50 TLE changes the medial temporal functional network p <.05 p < 10-4 I C SEED Maccotta et al., 2011, in preparation 50

51 TLE changes the medial temporal functional network p <.05 p < 10-4 I C SEED Maccotta et al., 2011, in preparation 51

52 TLE changes the medial temporal functional network p <.05 p < 10-4 I C SEED Maccotta et al., 2011, in preparation 52

53 TLE changes the medial temporal functional network p <.05 p < 10-4 I C TLE leads to specific decreases and increases in connectivity with the medial temporal regions, compared to controls SEED Maccotta et al., 2011, in preparation 53

54 TLE decreases coupling between medial temporal regions p <.05 p < 10-4 I SEED: C IPSILATERAL HIPPO HEAD IPSILATERAL HIPPO BODY IPSILATERAL PARAHIPPO Maccotta et al., 2011, in preparation 54

55 TLE decreases coupling between medial temporal regions p <.05 p < 10-4 I SEED: C IPSILATERAL HIPPO HEAD IPSILATERAL HIPPO BODY IPSILATERAL PARAHIPPO SEED: CONTRA- LATERAL HIPPO HEAD CONTRA- LATERAL HIPPO BODY CONTRA- LATERAL PARAHIPPO 55

56 TLE decouples the medial temporal regions CTL TLE - CTL 56

57 Does TLE strengthen any connections? 57

58 The insula Often involved in temporal seizures Hogan et al.,

59 The insula Often involved in temporal seizures Active at multiple and increasing levels of integration: Involved in control of heartbeat and other visceral functions 59

60 The insula Often involved in temporal seizures Active at multiple and increasing levels of integration: Involved in control of heartbeat and other visceral functions A seat for interoceptive representations ( body-sensing ) 60

61 The insula Often involved in temporal seizures Active at multiple and increasing levels of integration: Involved in control of heartbeat and other visceral functions A seat for interoceptive representations ( body-sensing ) Involved in perception of the self, self-awareness 61

62 The insula Often involved in temporal seizures Active at multiple and increasing levels of integration: Involved in control of heartbeat and other visceral functions A seat for interoceptive representations ( body-sensing ) Involved in perception of the self, self-awareness Involved in above-the-self perceptions, perception of the self over time, altered time perception 62

63 Insulae increase connection to the affected hippocampus I C SEEDS: Maccotta et al., 2011, in preparation 63

64 Insulae increase connection to the affected hippocampus I C SEEDS: Maccotta et al., 2011, in preparation 64

65 TLE changes the medial temporal network IPSILATERAL CONTRALATERAL INCREASED IN TLE DECREASED IN TLE Maccotta et al., 2011, in preparation 65

66 Impact on Clinical Care and Practice Characterizing the components of the functional network of TLE may lead to numerous contributions to epilepsy care: Prevention: can functional connectivity changes in the healthy predict development of the disease? 66

67 Impact on Clinical Care and Practice Characterizing the components of the functional network of TLE may lead to numerous contributions to epilepsy care: Prevention: can functional connectivity changes in the healthy predict development of the disease? Diagnosis: do specific functional connectivity abnormalities correlate with specific disease processes? Can they predict success of medical or surgical interventions? 67

68 Impact on Clinical Care and Practice Characterizing the components of the functional network of TLE may lead to numerous contributions to epilepsy care: Prevention: can functional connectivity changes in the healthy predict development of the disease? Diagnosis: do specific functional connectivity abnormalities correlate with specific disease processes? Can they predict success of medical or surgical interventions? Targets for intervention: are there nodes in the functional network that make it prone to epileptic seizures? Can we target them with surgery or intracranial neurostimulating devices? 68

69 Treatment Recommendations Characterization of changes in functional connectivity associated with epilepsy may lead to future changes in treatment recommendations, though at present this remains speculative 69

70 Treatment Recommendations Characterization of changes in functional connectivity associated with epilepsy may lead to future changes in treatment recommendations, though at present this remains speculative Changes in functional connectivity could be used to monitor effectiveness or appropriateness of specific medications in the treatment of specific epilepsy syndromes 70

71 Treatment Recommendations Characterization of changes in functional connectivity associated with epilepsy may lead to future changes in treatment recommendations, though at present this remains speculative Changes in functional connectivity could be used to monitor effectiveness or appropriateness of specific medications in the treatment of specific epilepsy syndromes Changes in functional could lead to potential new surgical targets, including both lesion-based or neurostimulation techniques 71