1. Functional Magnetic Resonance Imaging: Emerging Clinical Applications Heather A Wishart,PhD, Andrew J.Saykin,PsyD, Thomas W.McAllister,MD

2. Introduction  Magnetic Resonance Neuroimaging techniques are shedding new light on brain mechanisms and clinical management of various neurological and neuropsychiatric disorders.

3. Introduction BB rief Review of fMRI Imaging UU se of fMRI in clinical practice Precautions UU se of fMRI in clinical practice NN eurosurgery candidates SS chizophrenia CC ognitive Impairment and Alzheimer’s Disease TT raumatic Brain Injury MM ultiple Sclerosis RR esearch on Neuro-plasticity in the Adult Human CC onclusions

4. Review of fMRI  Most fMRI studies are based on the blood-oxygen-level- dependent (BOLD) method, where the MRI signal derives from local changes in the ratio of deoxygenated to oxygenated hemoglobin that occur during neural events.  Deoxy- and oxy-hemoglobin differ in their magnetic properties.  Statistical parametric maps are derived and overlaid on anatomical images reflecting statistically significant signal changes in different brain regions (1-4% signal change from control to event at conventional field strength.  fMRI has high spatial and temporal resolution permitting the observation of transient and prolonged neural events.

5. Use of fMRI in clinical practice~precautions  There are numerous technical issues that must be accounted for when applying fMRI to the clinical population.  The illness may make it impossible for the patient to remain still (movement disorders). This artifact can be addressed to some extent but may introduce other forms of error during post processing.  Patients with cognitive deficits may not be able to follow the test instructions. Extensive training and assurance during scanning may be useful and it is important not to presuppose that the presence of a neuropsychiatric disorder will necessarily adversely affect scanning.  Do group differences in brain activation reflect the disease or the simple fact that they were performing the task differently or incorrectly?  This may be addressed by using different levels of difficulty including those that can be completed equally well by patients and control subjects.

6.  Other problems that require consideration include disease related changes in the coupling of neural activity and the hemodynamic response***, as well as the presence of medications that alter psychological state or BOLD response in the patient group.  Precautions must be taken at the individual level when interpreting results for the planning of surgical interventions. ***FIG 1. A and B, Functional maps generated from the event-related, visually cued bilateral motor task for a patient with occlusion of the right internal carotid artery. Two axial images are shown with a cross-correlation threshold of r > 0.3. Note that the motor cortex ipsilateral to the lesion (right side) shows minimal or absent activation as a result of the occluded right internal carotid artery (blue circle), a finding corroborated by the blood flow velocity results of the transcranial Doppler US examination. 1 Use of fMRI in clinical practice~precautions

7.  Other problems that require consideration include disease related changes in the coupling of neural activity and the hemodynamic response***, as well as the presence of medications that alter psychological state or BOLD response in the patient group.  Precautions must be taken at the individual level when interpreting results for the planning of surgical interventions. *** A and B, Functional maps generated from the block motor task for a right internal carotid artery occlusion (same patients as in Figure 1). Two axial images are shown at the same anatomic level as that obtained for the event-related maps in Figure 1, but with a cross-correlation threshold of r > 0.45. Note the strong bilateral activation in the motor cortex. 1 Use of fMRI in clinical practice~precautions

8.  In other words the event-related scans made it appear as though there was no activity ipsilateral to the vascular occlusion, whereas the block design consisting of 30 second active intervals revealed bilateral activation as would have been expected.  “The vascular disease inherent to our patient population may have curtailed the increase in blood flow to the expected area of activation that normally occurs subsequent to motor activity” 1  1:( Hemodynamic Response Changes in Cerebrovascular Disease: Implications for Functional MR ImagingLeo M. Carusonea, Jayashree Srinivasanb, Darren R. Gitelmanc,d, M. Marsel Mesulamd and Todd B. Parrisha,c) Use of fMRI in clinical practice~precautions

9. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates  fMRI is used in the assessment of individuals about to undergo functional neurosurgery for example:[to identify particular regions in the brain which can be considered “functional organs at risk (fOARs)] (Medical Physics, Vol.34, No.4 pp.1176-1184, April 2007)  Resection (cut away) of seizure foci  Neoplasms (metastatic cancer foci) Neoplasia is the scientific term for the group of diseases commonly called tumor or cancer (From Wikipedia)  Vascular malformations

10. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates Resection of seizure foci "fMRI gives the surgical team an important roadmap of the brain function without contrast injections or invasive tests ”(http://www.sciencedai ly.com/releases/2005/06/050 628063632.htm)

11. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates Neoplasms (metastatic cancer foci) "fMRI gives the surgical team an important roadmap of the brain function without contrast injections or invasive tests ”(http://www.sciencedai ly.com/releases/2005/06/050 628063632.htm) Fig A. Fig B.

12. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates Vascular malformations "fMRI gives the surgical team an important roadmap of the brain function without contrast injections or invasive tests ”(http://www.sciencedai ly.com/releases/2005/06/050 628063632.htm)

13. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates Vascular malformations In a clinical setting two problems must be solved. First of all the exact localization on the brain of the cortical reorganization has to be demonstrated. This is done by means of a functional MRI. This is a classical MRI scan where two scans are combined : a normal brainscan and a scan performed during auditory exposure. http://www.oorsuizen.be/neurochir_EN.htm

14. Use of fMRI in clinical practice cont’d: Neurosurgery Candidates  fMRI is used in the assessment of individuals about to undergo functional neurosurgery for example:[to identify particular regions in the brain which can be considered “functional organs at risk (fOARs)] (Medical Physics, Vol.34, No.4 pp.1176-1184, April 2007)  Resection (Cut away) of seizure foci  Neoplasms (metastatic cancer foci) Neoplasia is the scientific term for the group of diseases commonly called tumor or cancer (From Wikipedia)  Vascular malformations  fMRI is used to Identify whether resection site is in or near critical regions for language, memory, or movement.  fMRI has been shown to have good agreement between Wada (intracarotid amobarbital) tests and electrical stimulation mapping which are invasive procedures.  fMRI yields additional intrahemispheric data and is not limited by lateralization of functions.  TO THE EXTENT POSSIBLE ACTIVATED AREAS AROUND LESION ARE AVOIDED DURING SURGERY

15. Use of fMRI in clinical practice cont’d: Schizophrenia  WHAT IS SCHIZOPHRENIA?  is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions or disorganized speech and thinking in the context of significant social or occupational dysfunction.  The symptoms of schizophrenia are often divided into two groups:Positive symptoms, for example, hallucinations and delusions. Negative symptoms, for example, flat affect, apathy and poverty of speech, social withdrawal, and depression. http://www.sfnsw.org.au/schizophrenia/symptoms.htm

16. Use of fMRI in clinical practice cont’d: Schizophrenia  fMRI has been used to extend scientific understanding of the neural basis of Schizophrenia.  Working memory cognitive deficits have been hypothesized to be a key cognitive deficit in some sub-types of Schizophrenia.  fMRI reveals reduced activation of frontal and parietal regions on working memory tasks in the patient group. Decreased brain activity in schizophrenia subjects (S) compared to normal controls(N) in an fMRI study examining executive functioning. Image courtesy of Prof. Philip Ward, NISAD Cognitive Neuroscience Research Panel. (http://www.schizophrenia.com/disease.htm)

17. Use of fMRI in clinical practice cont’d: Schizophrenia  fMRI replicates previous findings of hypofrontality.  These results also suggest that impaired activation of frontal regions during working memory task is related to thought disturbances: thought content- a result of fronto-parietal systems dysfunction.  Other studies have shown vis-à-vis medication-naïve patient samples increased brain activation compared with healthy control samples. (when medication and performance artifacts are taken into account).  An excessive recruitment of neural processing power during reasoning tasks may be associated with Schizophrenia.  Atypical antipsychotics may normalize this excessive activity.

18. Use of fMRI in clinical practice cont’d: Schizophrenia  In another study Muller et al. demonstrated excess subcortical activation during a simple motor task in untreated Schizophrenics compared to those treated with various antipsychotic agents and the healthy controls.

19. Use of fMRI in clinical practice cont’d: Schizophrenia  Zorrilla et al. recently found a group difference in activation patterns underlying memory for recent information in schizophrenia.  “The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices.” (http://arjournals.annualreviews.org/doi/abs/1 0.1146/annurev.neuro.27.070203.144130)http://arjournals.annualreviews.org/doi/abs/1 0.1146/annurev.neuro.27.070203.144130  Medial temporal activation was inversely related to subsequent recognition memory in healthy control individuals, the opposite pattern occurred in patients. http://www.nada.kth.se/~asa/bilder/MTL.jpg

20. Use of fMRI in clinical practice cont’d: Schizophrenia  Studies have also found:  A failure in patient groups in the coupling of reaction time and bilateral parietal activation that is seen in normal subjects.  In examining Schizophrenic patients’ deficit in interpreting the mental state of others (“theory of mind”) Russell et al. found less BOLD signal in the left inferior frontal gyrus in patients. http://content.answers.com/main/content/wp/en/thumb/0/00/250px-Inferior_frontal_gyrus.png

21. Use of fMRI in clinical practice cont’d: Schizophrenia  Converging lines of evidence show an interplay of brain structure and function and behavioral and environmental factors in the causation of such disorders. (RECIPROCAL DETERMINSM).  Abnormalities of brain structure and function may lead to symptoms (unidirectional view) but years of abnormal functioning and exposure especially during childhood development may lead to structural and functional abnormalities.  Bringing it together:  Mesolimbic (projections from limbic system to forebrain)- positive symptoms- shows higher activation in schizophrenics in a hypofrontality (negative symptoms) setting. Normal subjects only show this activation pattern in a threat situation. (http://www.annalsnyas.org/cgi/content/abstract/877/1/562)  QUESTION: (relative to the environment)  Do you think that abnormalities in higher cognitive functions (cortical) cause changes in mesolimbic activity (motivation/emotion eg. Fear)? Or do changes in mesolimbic activity subsequently cause functional and structural changes in the cortex? (resulting in thought disturbances)

22. Use of fMRI in clinical practice cont’d: Schizophrenia  PROBLEM: In some studies activation for patients did not remain stable across test-retest fMRI scans despite stable task performance. Thus many sources of variation exist in fMRI studies of schizophrenia.

23. Use of fMRI in clinical practice cont’d: Cognitive Impairment and Alzheimer’s Disease  What is Alzheimer's Disease?  Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's, is the most common type of dementia. Alzheimer's is a degenerative and terminal disease for which there is no known cure.  Research indicates that the disease is associated with plaques and tangles in the brain Histopathogic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of presenile onset. http://en.wikipedia.org/wiki/Image:Alzheimer_dementia_%283%29_presenile_onset.jpg

24. Use of fMRI in clinical practice cont’d: Cognitive Impairment and Alzheimer’s Disease  Episodic memory is a component of Declarative memory (remember medial temporal slide?)  Episodic memory impairment is a primary cognitive feature of Alzheimer's disease (AD). Consistent with pathologic and structural imaging fMRI shows evidence of reduced hippocampal formation activation in AD patients during episodic memory encoding. http://3d-brain.ki.se/atlas/images/limbic.jpg

25. Use of fMRI in clinical practice cont’d: Cognitive Impairment and Alzheimer’s Disease  In a study of visual stimuli encoding, Kato et al. compared young and older control individuals with mild AD patients and found that all subjects activated the visual cortex, but the patients failed to activate the entorhinal cortex as well as other temporal regions and frontal areas involved in episodic memory. They also showed reduced intrahippocampal functionality.

26. Use of fMRI in clinical practice cont’d: Cognitive Impairment and Alzheimer’s Disease  Reduced activation of frontal regions has been seen in AD patients during episodic memory retrieval; within this group hippocampal volume was related to preservation of frontal activation.  AD patients show greater spatial extent of frontal activation compared with control individuals on the same task. This increased activation was directly related to the degree of atrophy in the same brain region.  This supports the compensatory hyperactivation hypothesis which suggests that greater neuronal recruitment is required in AD patients to complete the same task as the control subjects even when their accuracy was the same or lower than the control group.  In neurologically intact individuals who carry a genetic risk for AD, increased activation in temporal, parietal, and prefrontal regions has been reported during episodic memory processing.  fMRI may someday serve as a biomarker method to potentially identify at-risk individuals early on in the disease process, and thus enable early biomedical interventions as they become available.

27. Use of fMRI in clinical practice cont’d: Traumatic Brain Injury (TBI)  fMRI studies of mild TBI in acute post injury period have shown differences in group activation associated with working memory despite equivalent task performance. Patients showed lower activation in low working memory demand condition and higher activation in high working memory demand condition than the control group. These findings may suggest TBI related neural processing changes corresponding to cognitive changes in these patients. (corresponding to patients subjective impressions of cognitive changes).  Lateralization of brain activation during working memory have also been demonstrated in moderate to severe TBI cases.  Though both groups activated frontal, parietal, and temporal regions the patients had a more dispersed activation and greater right hemisphere activation in frontal lobes. This corroborates recent findings that PTSD and TBI (with concussion) patients are likely to become severely depressed if left untreated. Higher activity in the right frontal and parietal lobe is associated with a later onset depression. (http://cat.inist.fr/?aModele=afficheN&cpsidt=15694558, &http://www.medicalnewstoday.com/articles/94564.php)

28. Use of fMRI in clinical practice cont’d: Multiple Sclerosis (MS)  WHAT IS MS? MS is known as disseminated sclerosis or encephalomyelitis disseminata) is an also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the immune system attacks the central nervous system (CNS), leading to demyelination. It may cause numerous physical and mental symptoms, and often progresses to physical and cognitive disability. fMRI studies of MS provide evidence of reallocation of brain processing resources associated with motor, sensory, and cognitive abilities even in patients with no impairment of functioning. These changes are associated with the structural and neurochemical alterations in the brain. Studies have shown increased, spatially shifted or expanded activation during motor tasks even when no motor deficit is present.

29. Use of fMRI in clinical practice cont’d: Multiple Sclerosis (MS)  Picture right (before MS)..Left with MS..Demonstrates areas which may Cause lateralization and functional changes in the CNS. http://www.msreversed.com/MRI/MRI_2004_12_(Small).jpg

30. Use of fMRI in clinical practice cont’d: Neuroplasticity in the adult brain  fMRI research suggests that the potential for adaptive plasticity (in response to trauma etc.) in the adult brain may have been underestimated for some time.  BOLD fMRI neuroimaging techniques in MS and AD are advancing the understanding of such plasticity.  These studies have revealed changes in patterns of activation that include displacement of foci, spatially expanded regions of activation around the areas normally used for said function, activation of distal regions in and outside the territory normally used for the task (may include diaschisis- a sudden inhibition of function. This is produced by an acute focal disturbance in an area of the brain, due to for example a stroke, at a distance from the original seat of injury, but anatomically connected with it through fibre tracts.)(http://en.wikipedia.org/wiki/Diaschisis)http://en.wikipedia.org/wiki/Diaschisis  Some studies indicate hypoactivation in local networks relative to control individuals.  Further research is needed to determine the extent to which these changes support normal function (the extent to which they are compensatory)

31. Conclusion  fMRI’s application to clinical research and clinical practice in neurology and psychiatry has the potential to improve understanding of brain- behavior relationships.  Relative to conventional MRI, fMRI has the potential to provide a more complete appreciation of both pathologic and reparative processes in the brain.  This information may be used in diagnosis, prognosis, and treatment monitoring and may be used in some conditions as a biomarker.  fMRI data will remain open to interpretation at the level of the individual patient.

32. The end.