**7. Other investigations and future prospectives**

Syncope associated to orthostatic hypotension, urinary incontinence and constipation is common symptoms in demented patients, mainly in DLB and in PDD. AD and FTD show less frequently autonomic dysfunction. There are non invasive tests including standard cardiovascular tests, 123I-MIBG cardiac scintigraphy, urodynamic tests, gastrointestinal motility studies, sweating reflexes and pupillary responses that assess autonomic dysfunction in these patients.

123I-MIBG is an analogue of the sympathomimetic amine guanethidine, which is used to determine the location, integrity, and function of postganglionic noradrenergic neurons [85]. Patients with PD can exhibit reduced cardiac 123I-MIBG-derived radioactivity without other evidence of autonomic failure, whereas those with DLB can have reduced cardiac 123I-MIBGderived radioactivity without evidence of parkinsonism [86]. 123I-MIBG may have the potential to differentiate PD from other causes of parkinsonism. For example, MSA and PSP pose a difficult diagnostic challenge.

In PD and DLB, LB are encountered in extracranial tissues, notably in autonomic ganglia [87]. Cardiac sympathetic degeneration can be demonstrated early in the disease process before motor symptoms. In 2005, the DLB Consortium concluded that diminished uptake of 123I-MIBG on cardiac scintigraphy was a ''supportive'' clinical feature that required more study [2].

Positron emission tomography (PET) utilizes biologically active molecules in micromolar or nanomolar concentrations that have been labelled with short-lived positron-emitting isotopes. The physical characteristics of the isotopes and the molecular specificity of labeled molecules, combined with the high detection efficacy of modern PET scanners, provide a sensitivity for human in vivo measurement of indicator concentrations that is several orders of magnitude higher than with the other imaging techniques. Whereas the very short halflives of O15 (2 min) and C11 (20 min) limit their use to fully equipped PET centres with a cyclotron and radiopharmaceutical laboratory, F18 labelled tracers (half-life 110 min) can be produced in specialized centres and distributed regionally to hospitals running a PET scanner only. Clinical use of PET is now well established in clinical oncology and it is therefore becoming widely available in major hospitals. In addition to its use in research, brain PET also provides diagnostically relevant information mainly in neurodegenerative disorders, focal epilepsy and brain tumors. In dementia, the measurement of cerebral

Is There a Place for Clinical Neurophysiology Assessments in Synucleinopathies? 319

between injection and scanning was just 3 hours, making the procedure possible on a single outpatient visit. Both ligands are cocaine analogues, which bind the dopamine reuptake and transporter molecule found in the presynaptic cell membrane of dopamine producing nigrostriatal nerve terminals in the striatum (caudate and putamen). Reduced binding reflects dysfunction or loss of nerve terminals, usually associated with loss of the neuronal cell bodies in the substantia nigra. Clearly, the test is not specific with regard to the nature of the pathology in the substantia nigra, but Lewy body pathology is the commonest cause of major bilateral loss of substantia nigra neurones, with loss of about 50% of neurones being necessary before parkinsonism becomes clinically detectable [92]. These studies show consistently and convincingly that in subjects with a clinical diagnosis of probable DLB, there is reduced binding of ligand in the putamen and caudate, and that in AD, the ligand binding is not significantly different from controls, suggesting strongly that FP-CIT SPECT would be effective in distinguishing DLB cases from AD cases when the distinction cannot be confidently made on clinical grounds. FP-CIT scans were abnormal in DLB cases without

The weakness of all the studies is that the diagnoses of DLB and AD were clinical, and therefore subject to error. An autopsy diagnosis has to be the gold standard, notwithstanding the uncertainties involved in the neuropathological diagnosis of both AD and DLB and the difficult issue of the coexistence of neuropathological features in both disorders. In applying the consensus clinical diagnostic criteria for probable DLB proposed by the consortium on DLB at their first international workshop, the greatest accuracy when compared with subsequent autopsy diagnosis was achieved by the Newcastle upon Tyne group (83% sensitivity, 95% specificity). The estimated sensitivity and specificity of FP-CIT SPECT scan abnormality for a diagnosis of DLB versus AD will obviously be affected by the extent to which patients are wrongly categorized clinically. Ideally every patient with dementia deserves a diagnosis as accurate as possible. Accordingly, in any patient whose dementia diagnosis is uncertain and who could possibly have DLB a dopamine transporter SPECT scan should be considered. Most such patients will fulfill clinical diagnostic criteria for ''possible DLB'' (dementia plus one core feature; or dementia plus one or more ''suggestive'' features, obviously excluding abnormal dopamine transporter scan which is currently one of the suggestive features). The effectiveness of FP-CIT in contributing to the diagnosis of DLB has recently been convincingly shown [94]. Most patients with clinically typical DLB do not need a FP-CIT scan. However, there are patients who fulfill diagnostic criteria for probable DLB, but are also affected by complicating medical issues such as cerebrovascular disease or are on medication with extrapyramidal adverse effects, and in such situations, a dopamine transporter scan can clarify the diagnosis. Finally, there are patients who have mild cognitive impairment (not dementia) and in addition have features raising the possibility of DLB (such as visual hallucinations, fluctuating cognition, and neuroleptic sensitivity). In these cases, recurrent delirium may be a concern, leading to repeated investigations. An abnormal FP-CIT scan can be diagnostically helpful and

Although there is a large and increasing body of knowledge on the genetic, molecular and cellular mechanisms of neurodegenerative disorders, the exact cause is unknown, except for a few rare genetic variants. Neurophysiological understanding could guide early differential diagnosis, and may suggest new ways to monitor treatment response. Since a few years the availability of whole-head MEG systems has expanded the scope of such studies. MEG can

parkinsonism, as well as in cases with parkinsonism [93].

possibly cost worthy.

glucose metabolism by 18F-2-fluoro-2-deoxy-Dglucose (FDG) and specific molecular imaging techniques involving tracers for amyloid and major neurotransmitters are of diagnostic interest. Brain PET using FDG is a firmly established technique for demonstration of regional functional impairment in neurodegenerative disease. AD is associated with typical regional impairment of posterior cortical association areas that allow very early diagnosis before clinical manifestation of dementia and monitoring of progression and treatment effects. DLB additionally involves metabolic impairment of the primary visual cortex. Predominant impairment of the frontal and anterior temporal regions is seen in FTD, primary progressive aphasia and semantic dementia. New perspectives are opened by tracers for imaging amyloids, which appear to be very sensitive for detecting even preclinical AD cases, although confirmation of the specificity remains to be demonstrated. Tracers for measuring local AChE activity and the binding capacity of nicotinic and serotoninergic receptors address neurotransmitter deficits in dementia. Impairment of dopamine synthesis that is characteristic for DLB can be demonstrated by 18F-fluorodopa PET. Pittsburgh compound-B (PIB)-PET imaging is a sensitive and specific marker for underlying β amyloid deposition and represents an important investigative tool for examining the relationship between amyloid burden, clinical symptoms and structural and functional changes in dementia. Amyloid imaging may also be useful for selecting patients for anti-amyloid therapies. However, studies have identified PIB-positive cases in otherwise healthy older individuals (10–30%), limiting diagnostic specificity. Development of biomarkers for investigating other aspects of dementia pathology, i.e. soluble β amyloid, tau protein, synuclein deposition and brain inflammation would further inform our understanding and assist in studying disease-modifying and preventive treatments in dementia. Both DLB and PDD are characterized at autopsy by the presence of subcortical and/or cortical Lewy bodies. It has been well established that often there is also a substantial burden of amyloid pathology, though, compared to AD, plaques are more often diffuse than dystrophic neurites [88]. A limited number of PET studies have examined the amyloid burden in DLB and PDD in vivo [89] and showed that in DLB mean brain PIB uptake was significantly higher than in controls, while uptake in PDD was comparable to controls and PD without dementia. In particular, 85% of DLB patients had significantly increased amyloid load in one or more cortical regions, whereas 83% of PDD patients had 'normal' PIB uptake. None of the PD patients showed any evidence of increased cortical amyloid deposition. A report by Gomperts and colleagues [90] revealed that cortical amyloid burden as measured by PIB was higher in DLB than in PDD, but similar to AD. The findings suggest that global cortical amyloid burden is high in DLB but low and infrequent in PDD. An increased amyloid burden could contribute to the rapid progression of dementia in DLB [89] while it may also play a role in the timing of dementia relative to the motor symptoms of Parkinsonism in DLB and PDD [88,90]. Either PET or SPECT can be employed to provide functional imaging of the nigrostriatal dopaminergic system in vivo. SPECT has the advantage of being more readily available and somewhat easier to organize and undertake, and the majority of the reported studies of imaging of the dopaminergic system in DLB have been SPECT studies, even though PET has produced equivalent results [91]. The first ligand used in SPECT was [123I]-2b-carbomethoxy-3b-(4-iodophenyl) tropane (b-CIT). Subsequently, [123I] N-x-flouropropyl-2b-carbomethoxy- 3b-(4-iodophenyl) nortropane (FP-CIT) became available. FP-CIT was preferable because the time interval

glucose metabolism by 18F-2-fluoro-2-deoxy-Dglucose (FDG) and specific molecular imaging techniques involving tracers for amyloid and major neurotransmitters are of diagnostic interest. Brain PET using FDG is a firmly established technique for demonstration of regional functional impairment in neurodegenerative disease. AD is associated with typical regional impairment of posterior cortical association areas that allow very early diagnosis before clinical manifestation of dementia and monitoring of progression and treatment effects. DLB additionally involves metabolic impairment of the primary visual cortex. Predominant impairment of the frontal and anterior temporal regions is seen in FTD, primary progressive aphasia and semantic dementia. New perspectives are opened by tracers for imaging amyloids, which appear to be very sensitive for detecting even preclinical AD cases, although confirmation of the specificity remains to be demonstrated. Tracers for measuring local AChE activity and the binding capacity of nicotinic and serotoninergic receptors address neurotransmitter deficits in dementia. Impairment of dopamine synthesis that is characteristic for DLB can be demonstrated by 18F-fluorodopa PET. Pittsburgh compound-B (PIB)-PET imaging is a sensitive and specific marker for underlying β amyloid deposition and represents an important investigative tool for examining the relationship between amyloid burden, clinical symptoms and structural and functional changes in dementia. Amyloid imaging may also be useful for selecting patients for anti-amyloid therapies. However, studies have identified PIB-positive cases in otherwise healthy older individuals (10–30%), limiting diagnostic specificity. Development of biomarkers for investigating other aspects of dementia pathology, i.e. soluble β amyloid, tau protein, synuclein deposition and brain inflammation would further inform our understanding and assist in studying disease-modifying and preventive treatments in dementia. Both DLB and PDD are characterized at autopsy by the presence of subcortical and/or cortical Lewy bodies. It has been well established that often there is also a substantial burden of amyloid pathology, though, compared to AD, plaques are more often diffuse than dystrophic neurites [88]. A limited number of PET studies have examined the amyloid burden in DLB and PDD in vivo [89] and showed that in DLB mean brain PIB uptake was significantly higher than in controls, while uptake in PDD was comparable to controls and PD without dementia. In particular, 85% of DLB patients had significantly increased amyloid load in one or more cortical regions, whereas 83% of PDD patients had 'normal' PIB uptake. None of the PD patients showed any evidence of increased cortical amyloid deposition. A report by Gomperts and colleagues [90] revealed that cortical amyloid burden as measured by PIB was higher in DLB than in PDD, but similar to AD. The findings suggest that global cortical amyloid burden is high in DLB but low and infrequent in PDD. An increased amyloid burden could contribute to the rapid progression of dementia in DLB [89] while it may also play a role in the timing of dementia relative to the motor symptoms of Parkinsonism in DLB and PDD [88,90]. Either PET or SPECT can be employed to provide functional imaging of the nigrostriatal dopaminergic system in vivo. SPECT has the advantage of being more readily available and somewhat easier to organize and undertake, and the majority of the reported studies of imaging of the dopaminergic system in DLB have been SPECT studies, even though PET has produced equivalent results [91]. The first ligand used in SPECT was [123I]-2b-carbomethoxy-3b-(4-iodophenyl) tropane (b-CIT). Subsequently, [123I] N-x-flouropropyl-2b-carbomethoxy- 3b-(4-iodophenyl) nortropane (FP-CIT) became available. FP-CIT was preferable because the time interval between injection and scanning was just 3 hours, making the procedure possible on a single outpatient visit. Both ligands are cocaine analogues, which bind the dopamine reuptake and transporter molecule found in the presynaptic cell membrane of dopamine producing nigrostriatal nerve terminals in the striatum (caudate and putamen). Reduced binding reflects dysfunction or loss of nerve terminals, usually associated with loss of the neuronal cell bodies in the substantia nigra. Clearly, the test is not specific with regard to the nature of the pathology in the substantia nigra, but Lewy body pathology is the commonest cause of major bilateral loss of substantia nigra neurones, with loss of about 50% of neurones being necessary before parkinsonism becomes clinically detectable [92]. These studies show consistently and convincingly that in subjects with a clinical diagnosis of probable DLB, there is reduced binding of ligand in the putamen and caudate, and that in AD, the ligand binding is not significantly different from controls, suggesting strongly that FP-CIT SPECT would be effective in distinguishing DLB cases from AD cases when the distinction cannot be confidently made on clinical grounds. FP-CIT scans were abnormal in DLB cases without parkinsonism, as well as in cases with parkinsonism [93].

The weakness of all the studies is that the diagnoses of DLB and AD were clinical, and therefore subject to error. An autopsy diagnosis has to be the gold standard, notwithstanding the uncertainties involved in the neuropathological diagnosis of both AD and DLB and the difficult issue of the coexistence of neuropathological features in both disorders. In applying the consensus clinical diagnostic criteria for probable DLB proposed by the consortium on DLB at their first international workshop, the greatest accuracy when compared with subsequent autopsy diagnosis was achieved by the Newcastle upon Tyne group (83% sensitivity, 95% specificity). The estimated sensitivity and specificity of FP-CIT SPECT scan abnormality for a diagnosis of DLB versus AD will obviously be affected by the extent to which patients are wrongly categorized clinically. Ideally every patient with dementia deserves a diagnosis as accurate as possible. Accordingly, in any patient whose dementia diagnosis is uncertain and who could possibly have DLB a dopamine transporter SPECT scan should be considered. Most such patients will fulfill clinical diagnostic criteria for ''possible DLB'' (dementia plus one core feature; or dementia plus one or more ''suggestive'' features, obviously excluding abnormal dopamine transporter scan which is currently one of the suggestive features). The effectiveness of FP-CIT in contributing to the diagnosis of DLB has recently been convincingly shown [94]. Most patients with clinically typical DLB do not need a FP-CIT scan. However, there are patients who fulfill diagnostic criteria for probable DLB, but are also affected by complicating medical issues such as cerebrovascular disease or are on medication with extrapyramidal adverse effects, and in such situations, a dopamine transporter scan can clarify the diagnosis. Finally, there are patients who have mild cognitive impairment (not dementia) and in addition have features raising the possibility of DLB (such as visual hallucinations, fluctuating cognition, and neuroleptic sensitivity). In these cases, recurrent delirium may be a concern, leading to repeated investigations. An abnormal FP-CIT scan can be diagnostically helpful and possibly cost worthy.

Although there is a large and increasing body of knowledge on the genetic, molecular and cellular mechanisms of neurodegenerative disorders, the exact cause is unknown, except for a few rare genetic variants. Neurophysiological understanding could guide early differential diagnosis, and may suggest new ways to monitor treatment response. Since a few years the availability of whole-head MEG systems has expanded the scope of such studies. MEG can

Is There a Place for Clinical Neurophysiology Assessments in Synucleinopathies? 321

in large-scale brain networks in neurodegenerative disorders such as PD and AD. Many MEG studies, most of which were conducted in the last five years, have confirmed and extended findings from previous EEG work. It is becoming clear that PD and AD show characteristic patterns of abnormal brain function, both locally as manifested by changes in spectral power, as well as at the scale of functional networks, manifested by changes in interregional synchronization. These changes may reflect abnormalities in specific networks and neurotransmitter systems, and could become useful in differential diagnosis and treatment monitoring. While MEG may be superior to EEG especially for functional connectivity studies, its high cost and the impossibility to combine it directly with structural MRI remain important obstacles. In this respect the development of ultra low field MRI (ULF MRI) could be a very interesting new approach [103]. If this technology can be further developed high quality integrated structural and functional studies of brain networks may become feasible. However, improvements on the acquisition side alone may not be sufficient for a better understanding of normal and disturbed brain networks. There is a urgent need for a proper theoretical framework for the analysis and interpretation of the data obtained with advanced functional imaging techniques. One attempt to deal with this problem is the application of graph theory to functional neuroimaging data [104]. This approach provides a theoretical framework for describing the structure and function of complex networks. Further studies along these lines, could help to advance our knowledge of disrupted brain

[1] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ; Work

[2] McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda

[3] Ince PG, McKeith IG. Dementia with Lewy bodies. In: Dickson DW, et al, editors.

Neurodegeneration: The molecular pathology of dementia and movement disorders. Basel: International Society of Neuropathology Press; 2003. p 188–199. [4] Bonanni L, Thomas A, Onofrj M. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2006;66:1455. [5] Bonanni L, Thomas A, Tiraboschi P, Perfetti B, Varanese S, Onofrj M. EEG

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Group on Frontotemporal Dementia and Pick's Disease. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol. 2001

JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec

networks in neurodegenerative disease.

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27;65(12):1863-72. Review.

**8. References** 

record brain activity directly, and has several advantages compared to conventional EEG recordings. In contrast to EEG, MEG is hardly affected by the skull, and does not require a reference electrode. Therefore, MEG may provide a more accurate image of ongoing brain activity. In addition, significant advances have been made in neuroscience concerning the understanding of oscillatory and synchronized brain activities. In particular it is now assumed that synchronization of neural activity between different brain regions may reflect functional interactions between these regions [95]. Such synchronization processes can be measured at the level of the scalp with EEG and even better with MEG. Interesting patterns of abnormal oscillatory activity and interregional synchronization have now been described in various brain disorders, including PD and AD [96].

One of the first MEG studies in PD was aimed at auditory evoked magnetic fields [97]; they suggest that this might reflect the combined effect of basal ganglia disease and auditory cortex degeneration. MEG studies were stimulated by the observation that PD may be associated with an increase in EEG coherence in the beta band, possibly due to the failure of a normal basal ganglia/thalamic drive to the cortex [98]. These changes were reversible after either dopaminergic treatment or deep brain stimulation. Functional connectivity was studied in the same large cohort of non-demented PD patients mentioned above using the synchronization likelihood [99]. In untreated, early phase PD patients a diffuse increase in functional connectivity in the lower alpha band was found. This abnormally high connectivity extended to other frequency bands, in particular the theta, upper alpha and beta bands, with progression of the disease. Disease severity was associated with abnormal connectivity in theta and beta bands. Cognitive perseveration was correlated with interhemispheric alpha band synchronization. In contrast to spectral changes, functional connectivity in PD does respond to treatment with L-dopa. Again, changes in demented PD patients are qualitatively different from those in non-demented PD patients. Demented PD patients showed a loss of functional connectivity, especially between the frontal and temporal areas within each hemisphere, and between the temporal areas of both hemispheres, in the alpha band [100]. Connectivity changes in dementia thus are on the decrease rather than on the increase trend, and a distribution that is more fronto-temporal compared to the central dominance of connectivity changes in non-demented PD. The overall pattern of connectivity changes in demented PD shows a similarity patterns found in studies on AD [101]. Although the number of MEG studies in PD is still very small, a consistent pattern of changes in local band power and interregional synchronization is becoming clear. Slowing of background activity (increased theta; decreased beta) and increased alpha band connectivity occur early in non-demented, drug naïve PD patients; with disease progression the spectral changes keep constant, whereas increased connectivity extends to other bands. Dopamine affects connectivity, but does not influence power. With the advent of dementia, slowing occurs in different frequency bands (increased delta power; loss of alpha power), and lower rather than higher connectivity is seen mainly in the alpha band. Changes in demented PD may be reversible after cholinergic rather than dopaminergic treatment. This characteristic pattern of progressive neurophysiological changes in non-demented and demented PD patients could reflect the progressive involvement of different neurotransmitter systems, as well as subcortical and cortical Lewy body pathology, during the course of the disease [102].

The advent of whole-head MEG systems, and the improvements in the understanding of oscillatory and synchronized brain activity, have opened up the way to study disturbances in large-scale brain networks in neurodegenerative disorders such as PD and AD. Many MEG studies, most of which were conducted in the last five years, have confirmed and extended findings from previous EEG work. It is becoming clear that PD and AD show characteristic patterns of abnormal brain function, both locally as manifested by changes in spectral power, as well as at the scale of functional networks, manifested by changes in interregional synchronization. These changes may reflect abnormalities in specific networks and neurotransmitter systems, and could become useful in differential diagnosis and treatment monitoring. While MEG may be superior to EEG especially for functional connectivity studies, its high cost and the impossibility to combine it directly with structural MRI remain important obstacles. In this respect the development of ultra low field MRI (ULF MRI) could be a very interesting new approach [103]. If this technology can be further developed high quality integrated structural and functional studies of brain networks may become feasible. However, improvements on the acquisition side alone may not be sufficient for a better understanding of normal and disturbed brain networks. There is a urgent need for a proper theoretical framework for the analysis and interpretation of the data obtained with advanced functional imaging techniques. One attempt to deal with this problem is the application of graph theory to functional neuroimaging data [104]. This approach provides a theoretical framework for describing the structure and function of complex networks. Further studies along these lines, could help to advance our knowledge of disrupted brain

#### networks in neurodegenerative disease.

#### **8. References**

320 Neuroimaging for Clinicians – Combining Research and Practice

record brain activity directly, and has several advantages compared to conventional EEG recordings. In contrast to EEG, MEG is hardly affected by the skull, and does not require a reference electrode. Therefore, MEG may provide a more accurate image of ongoing brain activity. In addition, significant advances have been made in neuroscience concerning the understanding of oscillatory and synchronized brain activities. In particular it is now assumed that synchronization of neural activity between different brain regions may reflect functional interactions between these regions [95]. Such synchronization processes can be measured at the level of the scalp with EEG and even better with MEG. Interesting patterns of abnormal oscillatory activity and interregional synchronization have now been described

One of the first MEG studies in PD was aimed at auditory evoked magnetic fields [97]; they suggest that this might reflect the combined effect of basal ganglia disease and auditory cortex degeneration. MEG studies were stimulated by the observation that PD may be associated with an increase in EEG coherence in the beta band, possibly due to the failure of a normal basal ganglia/thalamic drive to the cortex [98]. These changes were reversible after either dopaminergic treatment or deep brain stimulation. Functional connectivity was studied in the same large cohort of non-demented PD patients mentioned above using the synchronization likelihood [99]. In untreated, early phase PD patients a diffuse increase in functional connectivity in the lower alpha band was found. This abnormally high connectivity extended to other frequency bands, in particular the theta, upper alpha and beta bands, with progression of the disease. Disease severity was associated with abnormal connectivity in theta and beta bands. Cognitive perseveration was correlated with interhemispheric alpha band synchronization. In contrast to spectral changes, functional connectivity in PD does respond to treatment with L-dopa. Again, changes in demented PD patients are qualitatively different from those in non-demented PD patients. Demented PD patients showed a loss of functional connectivity, especially between the frontal and temporal areas within each hemisphere, and between the temporal areas of both hemispheres, in the alpha band [100]. Connectivity changes in dementia thus are on the decrease rather than on the increase trend, and a distribution that is more fronto-temporal compared to the central dominance of connectivity changes in non-demented PD. The overall pattern of connectivity changes in demented PD shows a similarity patterns found in studies on AD [101]. Although the number of MEG studies in PD is still very small, a consistent pattern of changes in local band power and interregional synchronization is becoming clear. Slowing of background activity (increased theta; decreased beta) and increased alpha band connectivity occur early in non-demented, drug naïve PD patients; with disease progression the spectral changes keep constant, whereas increased connectivity extends to other bands. Dopamine affects connectivity, but does not influence power. With the advent of dementia, slowing occurs in different frequency bands (increased delta power; loss of alpha power), and lower rather than higher connectivity is seen mainly in the alpha band. Changes in demented PD may be reversible after cholinergic rather than dopaminergic treatment. This characteristic pattern of progressive neurophysiological changes in non-demented and demented PD patients could reflect the progressive involvement of different neurotransmitter systems, as well as subcortical and cortical Lewy

in various brain disorders, including PD and AD [96].

body pathology, during the course of the disease [102].

The advent of whole-head MEG systems, and the improvements in the understanding of oscillatory and synchronized brain activity, have opened up the way to study disturbances


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**16** 

*Italy* 

**How fMRI Technology Contributes** 

Marta Olivetti Belardinelli1,2, MassimilianoPalmiero3

*2ECONA, Interuniversity Centre for Research on Cognitive Processing* 

*3Department of Internal Medicine and Public Health, University of L'Aquila 4Department of Neuroscience & Imaging, "G. d'Annunzio" University, Chieti* 

Mental imagery involves the generation of images using information stored in long-term memory, as opposed to the extemporaneous registration of information by our senses, giving rise to introspective experiences, such as 'seeing with the mind's eye', 'hearing with the mind's ear', 'smelling with the mind's nose'. In the past four decades, there has been much debate regarding the extent to which key elements of perception rely upon mental images versus propositional knowledge of sensory principles. Two contrasting approaches were developed i.e. perceptual and propositional theories. According to the perceptual approach, mental imagery is supported by mechanisms and processes involved in the actual perception. It functions as a modal analogue of that which is perceived by the senses (Kosslyn et al., 2006). Thus, mental images resemble perceptual information, e.g., visual images preserve both pictorial and spatial properties. According to the propositional approach, mental imagery is supported by abstract symbols of the sort used in a languagelike system. It functions as an a-modal description of the external world (Anderson & Bower, 1973; Pylyshyn, 1981, 2002, 2003). In particular, mental images rely on a code, structured by rules and relationships, rather than on mere verbal descriptions. Therefore, these mental images are epiphenomena of thought: instead of exhibiting the sensory aspects that determine their analogical nature, they are affected by "cognitive permeability," or the

tacit knowledge of physical laws in the external world (Pylyshyn, 1981, 2002).

These perspectives have primarily been investigated using visual imagery as a reference modality. After many years of behavioral research, the debate reached an impasse, as empirical evidence could only be explained by considering one of the two competitive approaches at a time (Kosslyn, 1980). The advent of neuroimaging techniques, particularly fMRI, offered the scientific community a new opportunity to solve the imagery debate. Unlike previous neuroimaging techniques, fMRI is capable of isolating many simultaneous and coordinated brain events with high spatial resolution. This facilitates the delineation of

**1. Introduction** 

*1Department of Psychology, "Sapienza" University of Rome* 

**to the Advancement of Research** 

**in Mental Imagery: A Review** 

and Rosalia Di Matteo2,4

*in Natural and Artificial System* 

