Psychiatry Research: Neuroimaging 140 (2005) 97–113 www.elsevier.com/locate/psychresns

Functional activation imaging in aging and

David Prvulovic a,*, Vincent Van de Ven a,b, Alexander T. Sack a,b, Konrad Maurer a, David E.J. Linden a,c,d

a Laboratory for Neurophysiology and Neuroimaging, Department of Psychiatry, Johann Wolfgang Goethe-Universita¨t, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt, Germany b Faculty of Psychology, Neurocognition, Maastricht University, Maastricht, The Netherlands c Max Planck Institute for Brain Research, Frankfurt, Germany d School of Psychology, University of Wales Bangor, United Kingdom Received 28 August 2004; received in revised form 6 January 2005; accepted 25 June 2005

Abstract

With life expectancy increasing continuously, the effects of neurodegeneration on brain function are a topic of ever increasing importance. Thus there is a need for tools and models that probe both the functional consequences of neurodegen- erative processes and compensatory mechanisms that might occur. As neurodegenerative burden and compensatory mechanisms may change over time, these tools will ideally be applied multiple times over the lifespan. Specifically, in order to elucidate whether brain-activation patterns in Alzheimer’s disease (AD) and in healthy aging follow general rules in the context of degeneration and compensation, it is necessary to compare functional brain-activation patterns during different states of neurodegeneration. This article integrates the findings of functional activation studies at different stages of neurodegeneration: in healthy aging, in subjects at high risk of developing dementia, in subjects with mild cognitive impairment (MCI), and in patients suffering from AD. We review existing theoretical models that aim to explain the underlying mechanisms of functional activation changes in aging and dementia, and we propose an integrative account, which allows for different neural response patterns depending on the amount of neuronal damage and the recruitment of compensatory pathways. D 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Alzheimer’s disease; Functional magnetic resonance imaging; Positron emission tomography; Cortical reserve capacity

1. Introduction

Alzheimer’s disease (AD) is the most common cause of dementia. The age-related exponential * Corresponding author. Tel.: +49 69 6301 7634; fax: +49 69 increase of the incidence of AD (Jorm and Jolley, 6301 3833. 1998) gives evidence for a close relation between E-mail address: [email protected] (D. Prvulovic). AD and aging. The course of AD is characterised

0925-4927/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2005.06.006 98 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 by a unique progression of clinical (e.g. Almkvist dementia-related degenerative processes increase and Winblad, 1999) and neuropathological (Braak over time. These complex relations have so far and Braak, 1991) features that separates AD from not been investigated systematically. Ideally, a com- bnormal agingQ. Furthermore, some evidence sug- bined longitudinal study would be needed, tracking gests that brain regions differ in their vulnerability subjects from early adulthood to old age and during to age-related and to AD-related degenerative pro- different stages in the course of dementia (including cesses (Raz et al., 2004; Small et al., 2004). How- mild cognitive impairment). Additionally a para- ever, although the spatial distribution, extent, time metric task design should be applied to test for of onset and velocity of progression of neurodegen- interactions between different levels of neuronal eration differ in aging and dementia, both lead to damage and different levels of task demand. How- progressive synaptic dysfunction and synaptic loss ever, this approach is cumbersome and lengthy, and (Adams, 1987). It has thus been hypothesized that it has not been applied so far. As a substitute, we even normal aging may result in dementia when a will try to derive some general insight about the threshold of synaptic loss has been reached, pro- interactions between neurodegeneration and brain vided that the lifespan is long enough (Terry and activation by reviewing existing cross-sectional stu- Katzman, 2001). dies that compared demented patients with non- Synaptic integrity and function are closely related demented subjects or old with young participants. to cognitive, motor and sensory performance (e.g. Some of these studies also investigated healthy Luebke and Rosene, 2003). Synaptic function is subjects at high genetic risk of developing AD furthermore the basis of measures of brain activation and subjects with mild cognitive impairment. The as revealed by regional metabolic, blood flow or latter groups are both considered to reveal a neuro- BOLD-signal changes (Logothetis et al., 2001). pathological burden that has not reached the thresh- Since the predominant impairment of temporo-parie- old of clinically manifest AD. A subgroup of those tal regional glucose metabolism (rCMRglu) and affected is supposed to represent preclinical stages blood flow (rCBF) during the resting state has of AD. We discuss the heterogeneous functional been established as an early and reliable diagnostic imaging findings on healthy aging, dementia, and marker in AD (e.g. Frackowiak et al., 1981; Duara et at-risk populations in the light of existing models of al., 1986; Silverman et al., 2001), this review will cognitive reserve capacity and functional compensa- focus on the recent advances made by functional tion. Finally, we propose an integrated account that activation studies (Almkvist, 2000), which investi- relates functional activation changes in aging and gate the response of the brain to external stimulation dementia to the level of neurodegeneration, task or cognitive tasks. This approach may provide dee- demand, and task performance. per insights into the impact of neural degeneration on the function of the cortico-subcortical networks of perception and cognition. 2. Review of functional activation studies The neuronal activity that is needed to perform a task usually depends on the task demands and 2.1. Functional activation studies in healthy aging increases with parametric changes in task difficulty. In the context of aging and dementia, however, the A number of functional activation studies have subjective task demand is additionally influenced by compared brain activation patterns during sensory, the amount of damage to the brain structures that motor and cognitive processing between young and are involved in task processing. With increasing older healthy adults. While the results seem to be regional damage, compensatory mechanisms such rather heterogeneous at first, they converge on several as the recruitment of additional areas will be points: required to perform the task. The interaction between task difficulty, different levels of synaptic – Studies that required the subjects to perform very damage and task performance is thus not only simple motor tasks or used passive sensory stimu- complex but also very dynamic as aging- and lation revealed decreased activation of the involved D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 99

sensory or motor cortical regions in older subjects 2.2. Functional activation studies in subjects at compared with younger adults (Cerf-Ducastel and genetic risk to develop AD Murphy, 2003; Suzuki et al., 2001; Ross et al., 1997; Yousem et al., 1999; Hesselmann et al., ApoE 4 has been identified as a susceptibility gene 2001; D’Esposito et al., 1999). that significantly increases the rate of clinical mani- festation of familial late-onset and sporadic AD and – Even when simple motor tasks were used, addi- decreases the mean age of onset (see Strittmatter and tional attentional or cognitive effort led to marked Roses, 1995). Although not all carriers of ApoE e4 increases of activation across motor, premotor and develop AD, it has been shown that middle-aged and other cortical regions in older compared with even young adults with ApoE e4 exhibit abnormal younger subjects (Mattay et al., 2002). brain metabolism that is in part similar to regional resting state metabolic decreases found in AD – In visual perceptual studies older subjects showed (Reiman et al., 1996, 2004). When compared with decreased activation in the occipital but increased blow-riskQ subjects, cognitively intact subjects who activation in prefrontal cortex (Grady et al., 1994; have an increased genetic risk of developing AD Madden et al., 1997). Grady and Craik (2000) have shown deviant functional activation patterns also demonstrated that older subjects, when com- depending on the particular cognitive task. No activa- pared with young adults, recruited different cortical tion differences between high- and low-risk subjects and subcortical regions (hippocampus, thalamus) were found during an auditory attention task (Burgg- during a face-recognition task and that their ren et al., 2002). In contrast, high-risk subjects performance correlated with this compensatory revealed a significantly higher amount and extent of activation. hippocampal, prefrontal and parietal cortex activation during a verbal learning task when compared with – The so called bHAROLDQ phenomenon (hemi- low-risk subjects (Bookheimer et al., 2000). Finally, spheric asymmetry reduction in old adults [Cabeza, in semantic and verbal fluency tasks, high-risk sub- 2001]): While young adults show a hemispheric jects showed decreased activation in temporal (Smith encoding/retrieval asymmetry (HERA) (Tulving et et al., 1999) and increased activation in parietal cortex al., 1994) with higher left prefrontal activation (Smith et al., 2002). during episodic encoding and higher right prefron- tal activation during retrieval, this asymmetry is 2.3. Functional activation studies in patients with decreased in older adults (Cabeza et al., 1997; mild cognitive impairment Ba¨ckman et al., 1997; Madden et al., 1999). The reduced lateralization of prefrontal cortex activity Mild cognitive impairment (MCI) is characterised in older participants was shown to aid performance by subjective complaints, impaired perfor- of a verbal working memory task, possibly indicat- mance on memory tests, normal general cognitive ing compensatory recruitment of the non-dominant function, and absence of additional criteria for demen- hemisphere (Reuter-Lorenz et al., 2000). tia (Petersen et al., 1999). The annual conversion rate from MCI to AD is estimated at 10%–15% (e.g., – In a study of regional metabolic activity with Artero et al., 2003). However, some proportion of fluorodeoxyglucose-PET (FDG-PET), Hazlett et MCI subjects do not seem to develop AD at all. In al. (1998) found a decrease of frontal task- the course of AD, memory and learning deficits are related activation during a verbal memory task usually amongst the very first symptoms to occur. The with increasing age. Interestingly, a re-analysis development of cognitive deficits is assumed to be of the same sample based on a division into related to the specific progression of neurofibrillary good and bad performers revealed that young accumulation that starts in entorhinal cortex and good performers had strong frontal activation, spreads to the hippocampus and other limbic struc- while old good performers had strong occipital tures that are critically involved in memory processing activation. (Braak and Braak, 1991). On the basis of its phenom- 100 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 enology and natural history, MCI can thus be regarded encoding when compared with age-matched healthy as a preclinical stage of AD in those patients who senior subjects (Machulda et al., 2003). actually develop AD during the subsequent years. In all other cases that do not end in dementia, the isolated 2.4. Functional activation studies in patients with memory dysfunction in MCI might not be related to manifest AD AD-specific pathology and thus may represent a sepa- rate entity. Memory is one of the first cognitive systems to be In a very intriguing study by Small et al. (1999), affected in AD. In memory tasks that engage visual senior subjects with and without memory complaints and verbal encoding, AD patients consistently reveal and AD patients participated in a visual memory marked activation deficits in the hippocampal forma- encoding task. While AD patients showed strongly tion and in frontal and temporal neocortex (Small et reduced task-related activation across all investigated al., 1999; Kato et al., 2001; Rombouts et al., 2000; regions of the hippocampal formation, participants Schro¨der et al., 2001; Sperling et al., 2003; Machulda with isolated memory complaints showed reductions et al., 2003). Hippocampal activation deficits in AD either in the subiculum or in the entorhinal cortex. The patients have also been found during olfactory mem- authors of this study suggested that the subgroup that ory tasks (Buchsbaum et al., 1991). revealed underactivation in the entorhinal cortex (EC) When the task-related activity was measured dur- might represent preclinical AD because of the early ing retrieval from memory, AD patients showed involvement of this area in AD pathology. Similarly, whole brain activation deficits (Kessler et al., 1991) the hippocampal formation was found to be less active or reduced activation in hippocampus and parietal in MCI subjects and AD patients during memory cortex (Ba¨ckman et al., 1999). Ba¨ckman et al.

Fig. 1. Relative contribution maps from group general linear model (GLM) analysis in 14 AD patients (right side) and 14 age-matched healthy control subjects (left side). Red color indicates task-related activation in favor of a visuospatial task (discrimination of angle sizes) vs. a visuomotor control task. Both groups did not differ in their performance on the tasks. AD patients revealed less task-related activation in bilateral superior parietal cortex (upper part of the picture) and more activation in left inferior temporal cortex when compared with the control group (lower part of the picture). D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 101

(1999) additionally found increased activation in left longer to respond to items presented during a visual prefrontal cortex in AD patients. Grady et al. (2003) working memory task revealed higher activation in demonstrated extended activation in bilateral prefron- parietal cortex than those who had lower response tal and temporo-parietal areas in AD patients during latencies (Honey et al., 2000). A similar relationship episodic retrieval as opposed to only left prefrontal between reaction times and functional activation was and temporal areas activated by control subjects. also found in visuospatial tasks (Ng et al., 2001). In short-term memory studies, the results are some- When discrimination of visual features was difficult what more complex. AD patients and controls demon- in visual perceptual tasks, healthy young subjects strated similar activation patterns when a verbal showed additional activation in prefrontal cortex working memory task was not difficult (3-word repe- (PFC, especially in the right hemisphere) during tition); however, at a more difficult level (8-word visual perceptual and memory tasks, even when repetition), AD patients showed higher activation in their accuracy was compromised at higher difficulty prefrontal and inferior parietal cortex (Becker et al., levels (Grady et al., 1996; Barch et al., 1997; 1996). In contrast, when a visual working memory Sunaert et al., 2000). Right PFC has been associated task (face recognition) was used, prefrontal activation with supervisory and attentional functions (Paus et was not higher in AD patients than in controls. al., 1997; Elliott et al., 1999), and its activation Instead, AD patients revealed higher activation in increases in parametric tasks have been suggested left medial temporal regions, comprising hippocam- to reflect task difficulty (Sunaert et al., 2000). pus and amygdala. Grady et al. (2001). Task-related activation across multiple association In visual perceptual tasks the results depend and sensory cortical areas can also be modulated by greatly on the tasks used. During passive visual sti- attention. For example, stimulus-related activation in mulation, AD patients revealed activation deficits in striate and extrastriate visual areas is enhanced when middle temporal and occipital cortex (Mentis et al., attention is focused on the corresponding areas in the 1996). In a face-matching task, Grady et al. (1993) visual field (Tootell et al., 1998). While the attentional found higher activation in frontal areas (frontal eye enhancement of brain activation in some cases seems field) and occipital pole in AD patients. Functional to follow an ball or nothingQ rule, a linear correlation activation related to angle discrimination was signifi- has been found between attentional load and task- cantly decreased in parietal cortex but increased in related functional activation in many brain regions occipitotemporal cortex in AD patients compared with (Culham et al., 2001). As a general rule in healthy healthy controls (Prvulovic et al., 2002, Fig. 1). young volunteers, areas subserving a cognitive task show increased or extended activation, and/or addi- tional areas are recruited with increasing task diffi- 3. Impact of performance and task difficulty on culty (Grasby et al., 1994; Carpenter et al., 1999; functional activation Sunaert et al., 2000; Vannini et al., 2004). How do the findings in healthy senior subjects The impact of task performance and task diffi- and patients compare with regard to the activation– culty on functional activation studies in healthy performance relationship? Morcom et al. (2003) young participants indicates a complex relationship compared the subsequent memory effect (i.e., between performance in a cognitive task and task- increased functional activation during successful related functional brain activation. During memory memory encoding compared with unsuccessful encoding, higher activation in the medial temporal encoding) between healthy young and older subjects. lobe and frontal areas strongly correlated with the They found that bilateral prefrontal activation was rate of successful retrieval (Wagner et al., 1998; associated with successful encoding in the senior Brewer et al., 1998; Kirchhoff et al., 2000), indicat- subjects as opposed to only left hemispheric prefron- ing that successful processing is reflected by higher tal activation in the young group. Moreover, only the activation than unsuccessful task processing. How- young subjects showed activation increases in left ever, higher activity may also indicate a longer time temporal cortex that correlated with successful spent on the task. For example, subjects who needed encoding. 102 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113

In a remarkable study of MCI patients, Dickerson by attention (e.g., in visual perceptual tasks) or c) et al. (2004) measured functional activation patterns more time-consuming and more difficult (perceptual during episodic memory encoding. They demon- discrimination tasks and memory tasks with increas- strated that the extent of activation in the medial ing load). These rules may also account for altered temporal lobe correlated with better memory perfor- functional activation responses in patients with declin- mance. Additionally, they found that activation was ing brain function (i.e., aging, at-risk state and man- most extended in patients with the worst clinical state ifest dementia) where task difficulty is influenced not at the time of the measurement and in those who only by parametric manipulations of the task but showed the fastest cognitive decline during follow- (most importantly) also by the level of neurodegen- up. This finding may result from higher task demand eration. The progression of neurodegeneration can in the more impaired subjects who, in turn, revealed either lead to elevated or extended activation (accom- additional compensatory recruitment of adjacent neu- panying unaffected or mildly impaired performance) ronal tissue in order to maintain task performance. or to activation deficits (often with severely impaired Similarly, healthy subjects at high risk to develop AD performance) and thus explain the apparently conflict- (Bookheimer et al., 2000; Smith et al., 2002) and even ing findings of hyperactivation and hypoactivation in AD patients (Woodard et al., 1998) showed a higher old age or cognitive impairment due to dementia. extent of functional activation than healthy controls when they maintained good task performance. In most functional activation studies that compared 4. Models and hypotheses for the interpretation of AD patients with age-matched healthy controls, lower functional activation effects in aging and dementia task performance in AD patients was accompanied by significant activation deficits (Rombouts et al., 2000; 4.1. Review of existing models Schro¨der et al., 2001; Kato et al., 2001; Sperling et al., 2003). In a study that compared healthy young and Even after the consideration of confounding fac- older participants, a subgroup of older subjects with tors such as task difficulty, altered baseline activa- reduced task performance revealed activation deficits tion and task performance, it remains difficult to during memory encoding in medial temporal lobe understand why dementia patients sometimes show (MTL) when compared with young subjects, even more task-related activation than healthy controls when only the successful trials were considered and sometimes less, in the same cortical regions. (Daselaar et al., 2003). The authors of this study Several models have been proposed in order to related this finding to MTL dysfunction in memory- integrate some of the basic mechanisms that link impaired older subjects. In the specific cases where the damage to cortical systems to their functional functional activation during rehearsal (Woodard et activation patterns. Logan et al. (2002) proposed al., 1998)orretrieval from memory (Ba¨ckman et bunder-recruitmentQ and bnon-selective recruitmentQ al., 1999) was measured, AD patients showed as possible mechanisms that may play a role in the extended task-related activation despite normal or observed changes of activation patterns during mem- impaired performance. During a working memory ory-related cognitive processes in healthy aging. task (including encoding and retrieval), Grady et al. This model summarizes the inability of the aging (2001) found that task-related functional activation in brain sufficiently to engage specific cortical regions the right PFC correlated with better performance in during cognitive performance. In order to compen- healthy old subjects as well as AD patients, while sate for this failure, additional areas that had origin- activation increases in the amygdala were correlated ally not been designated for the specific task are with better performance only in AD patients. recruited and become activated. This model would In sum, under normal conditions, when brain func- explain task-related activation of additional areas in tion is not altered by neurodegeneration or aging, older than in younger subjects. Yet, this model can increased or extended functional activation might also be applied to functional activation studies of indicate that the underlying neuronal processing is preclinical or already demented patients. Fig. 1 a) successful (e.g., in memory encoding), b) enhanced documents that AD patients fail to activate the D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 103 parietal cortex to the same extent as controls during indicate a degenerate system with one sufficient part visuospatial processing (Prvulovic et al., 2002). being damaged and other parts being activated Instead, they recruit an area less specific for visuos- instead, especially if the unexpected activation corre- patial computation (the fusiform gyrus). However, lates with performance. This concept works very well the parietal cortex is unspecifically overactivated in for circumscribed brain lesions (e.g., focal temporal at-risk patients during a verbal fluency task (Smith atrophy in semantic dementia). Yet, when neural et al., 2002). damage is more global, as in AD, it is more likely Some functional activation studies of AD (Grady et that all subsystems of a degenerate system will be al., 2003) and healthy aging (Hazlett et al., 1998) also impaired, leading to global activation deficits or non- revealed very distinct cortical activation patterns, specific (baberrantQ) activation patterns across the which correlated with performance benefits. It can brain, which no longer support normal performance. thus be assumed that, faced with the impaired access While these models of compensatory activation to specific task-subserving areas, the damaged brain and degeneracy explain the recruitment of different can under certain circumstances engage alternative areas in patients and controls, additional theoretical pathways in order to maintain successful task perfor- assumptions are required to explain why in different mance. These observations can be interpreted with a studies with AD patients, the same brain areas are view to the theory of bdegenerate systemsQ, which is sometimes overactivated and sometimes underacti- based on the ability of different structures to subserve vated. Rapoport and Grady (1993) introduced the the same function. This theory has been discussed model of a sigmoidal relation between regional cere- with reference to several biological systems, cognitive bral blood flow (rCBF) ( y-axis) and a function of task networks being a particularly prominent example difficulty and individual task performance (x-axis). In (Tononi et al., 1999; Price and Friston, 2002). When this model, several degrees of neuronal damage are different neuronal systems are sufficient to perform a implemented, which alter the shape of the brain cognitive task each on their own, the damage to only response curve. In early stages of the disease, patho- one or a subset of those systems will have no adverse logical damage shifts only the rising phase of the effect on task performance but lead to important sigmoidal brain response curve to the right. This differences in the brain-activation pattern. This reflects the finding that AD patients show reduced would explain why in functional activation studies rCBF during rest or during control tasks with very low not all healthy individuals activate the exact same processing demand. Consequently, the task-related brain regions during the same task, and why patients increase of rCBF during highly demanding tasks with lesions within areas that are usually activated would often be higher in early AD than in controls. during a cognitive task often have preserved perfor- In their model, early AD patients ultimately reach the mance. Task performance will only be impaired when same absolute amount of task-related rCBF as con- a necessary neuronal system has been damaged that trols. With increasing neuronal damage, the maximum cannot be compensated by any other system or when activation capacity of the brain decreases, and AD the complete set of degenerate systems is affected. patients reach a lower maximum rCBF in activated This model is complementary to that of Logan et al. states than controls. However, the model by Rapoport (2002) in that it introduces the distinction between and Grady (1993) concentrates on the response beha- neuronal systems that are sufficient and those that are viour of a cortical region without further consideration necessary for a particular cognitive task. For example, of its embedding in a network. a lesion to either the left or the right anterior temporal lobe (which are assumed to be separate systems, both 4.2. Integrative model for the interpretation of func- of which are sufficient for semantic processing) does tional activation in aging and dementia not impair the performance in semantic tasks, while lesions to both left and right anterior temporal cortex The previously described models explicitly consid- do (Mummery et al., 2000; Price and Friston, 2002). ered distributed specific (degenerate systems, Price Activation in brain regions that are usually not acti- and Friston, 2002) or unspecific coactivation (Logan vated by the investigated cognitive task might thus et al., 2002), but they did not account for the multiple 104 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 response patterns within the specifically affected area with a measurable behavioural response (reaction (Rapoport and Grady, 1993). Hence, it may be useful time, accuracy), whereas experiments that merely to combine some elements of all three approaches into involve passive stimulation or resting state measure- an integrated model (Fig. 2). Our model attempts to ments do not fall within its scope. clarify the heterogeneous findings of functional acti- The central element of the model (Fig. 2)isa vation studies (both PET and fMRI) in AD and aging, cortical region (processing unit: PU) that is part of and to overcome the restrictions of the former models. a cortical circuitry required for successful processing It addresses the different response patterns of cortical of the task at hand. The functional activation in the regions to increasing task demand. Additionally it PU at any given time point is dictated by the number considers various possible ways of interaction of subunits within the PU (e.g. single neurons or between brain regions in relation to brain damage populations) recruited at this time point. Increasing and compensatory mechanisms. This model was task difficulty will lead to increased total activation of designed to explain activation patterns in experiments the PU until the task difficulty exceeds the maximal

frontal / parietal attention systems MOD

PU

Functional Task activation performance (accuracy)

INPUT OUTPUT

Task difficulty

AUX specific or unspecific alternative pathways

Normal activation response Functional activation in slightly damaged PU Functional activation in severely damaged PU Task performance in normal functional system Task performance in slightly damaged functional system Task performance in severely damaged functional system

Fig. 2. An integrated model of possible relations between damage to a processing unit, the dynamics of its activation response in relation to task difficulty, and the integrated network engaged during the processing of a cognitive task (see text). For purposes of simplification, possible feedback loops are not considered. PU = processing unit; MOD = modulation unit; AUX = auxiliary unit. The relation between task performance and task difficulty is also integrated (red lines). D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 105 processing capacity (=total number of functioning regions being activated in AD (Prvulovic et al., 2002; subunits) of the PU. Consequently, the amount of Grady et al., 2001). The use of auxiliary pathways may available functional subunits at a certain level of reflect a different processing strategy. Moreover, the task demand can be termed bfunctional reserve proposed model of auxiliary pathways conforms to the capacityQ. The reserve capacity, or buffer, partly finding that aged and demented patients lose hemi- determines how much additional task difficulty can spheric asymmetry during encoding and retrieval, be mastered without loss of task performance or, in (Ba¨ckman et al., 1997; Madden et al., 1999; Reuter- cases of neurodegeneration, how much damage to the Lorenz et al., 2000). In terms of the degeneracy con- subunits and their connections can be sustained. In cept, the auxiliary pathway would represent a separate terms of metabolic parameters, the processing in the system that is capable of sufficiently processing the PU will lead to higher local glucose consumption as task. In terms of Logan’s compensation model (Logan well as to increased local blood flow and to an et al., 2002), the auxiliary pathway is less specific for a increased amount of oxygenated haemoglobin particular cognitive task than the PU and can thus only (BOLD signal change) in the vascular bed. All partly compensate for performance deficits. these changes lead to bactivationQ that can be mea- The amount of activation in the PU itself is deter- sured with PET, SPECT or fMRI. The system further- mined by the relation between its processing effi- more comprises an INPUT module, a cortical region ciency (the integrity of processing within single that provides information that is essential for the PU subunits of the PU and the integrity of communication to process the task, and a unit (MOD) that can between subunits within the PU), its processing capa- modulate the activity of the PU. Modulatory effects city (the number of subunits), the task difficulty, the can consist in a direct enhancement of processing task performance of the subject, and the quality of the efficiency in the PU or of the amount or the quality input signals. Processing efficiency impacts the slope of the input signal into the PU (e.g., attentional of functional activation, while processing capacity modulation). For instance, Woodard et al. (1998) limits the maximum of functional activation that can showed additional activation of parietal attention- be reached in the PU. These five factors together related regions in AD patients during a memory determine the work load of the PU in a specific task compared with age-matched controls, suggesting task. Depending on the combination of these factors, that in these patients successful task performance was two main scenarios can occur: supported by increased attentional effort. Prefrontal cortex (PFC) activation is related to attentional load 1. Decreased processing efficiency in combination and can enhance the performance of different cogni- with almost preserved processing capacity and tive tasks. Conversely, the failure of attentional input will lead to a compensatory recruitment of enhancement due to deficient PFC activation or to an increased number of subunits within the PU disrupted connections between the PFC and other to compensate for the diminished processing parts of the neural network involved in memory efficiency (dashed functional activation curve in encoding can lead to impaired processing. The obser- the PU, Fig. 2). The resulting work load is vation of Grady et al. (2001) that AD patients higher than normal and leads to increased total revealed a significantly impaired functional connec- activation in the PU (e.g., Bookheimer et al., tivity between frontal and temporal areas during a 2000). Because an impairment of processing visual working memory task is a case in point. capacity and the consequent higher work load However, if task processing cannot be sufficiently automatically lead to a reduced breserve conducted by the PU, other brain areas that initially are capacityQ in the PU, the limits of the processing not directly related to PU and that are more or less capacity of the PU will be reached earlier with specific for the processing of the task may become increasing task difficulty and thus lead to earlier involved (auxiliary pathway: AUX) in order to partly decompensation of task-performance (dashed red or completely compensate for the insufficient output line in Fig. 2). Findings from studies investigat- from the PU. This effect has indeed been shown in ing the effects of practice on functional brain functional imaging studies, with additional cortical activation support this view (for review, see 106 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113

Linden, 2003). In most perceptual and cognitive of the processing efficiency in a specific region can paradigms, practice leads to decreased activation, induce different compensation mechanisms within indicating more efficient and thus less effortful and/or outside the concerned region. These mechan- processing (e.g., Haier et al., 1992; Schiltz et al., isms include the recruitment of a higher number of 2001). neurons (or neuronal populations) (increasing peak 2. A greater amount of damage in the PU with a activation and/or spatial extent) and the coactivation significant decrease of processing capacity or dis- of specific or less specific remote areas, which can ruptions of the input channel(s) to the PU (Morri- either directly take over a part of the processing son et al., 1991) will lead to diminished activation burden (auxiliary pathway) or facilitate the task pro- in the PU (dotted black functional activation curve, cessing in the affected region. To what extent these Fig. 2) (e.g. Small et al., 1999; Smith et al., 1999; compensatory mechanisms will come into play Schro¨der et al., 2001). In this scenario, only a small seems ultimately to depend on the specific combina- part of the PU can be recruited for task processing. tion of several biological and study-related factors, While in very simple tasks performance might be including the task difficulty, the functional speciali- preserved, even slight increases of task difficulty sation of a damaged brain area, its natural contribu- will lead to a fast decrease of task performance tion to the cognitive task, the amount of damage, the (dotted red line in Fig. 2). The importance of pre- quality of the input, and the recruitment of potential served input channels has been shown by McCon- alternative processing pathways. Cholineacetyltrans- nell et al. (2003), who demonstrated that direct ferase (CHAT) activity has been found to be up- electromagnetic stimulation of the motor cortex regulated in some parts of the brain in patients leads to similar activation in old and young sub- with MCI (DeKosky et al., 2002). This finding has jects, whereas motor activity resulting from volun- been interpreted as a compensatory mechanism in tary finger tapping is decreased in old subjects preclinical AD stages. Compensatory processes of (Hesselmann et al., 2001). Impaired functional con- this type might account for the steeper slope of nectivity might be an indicator of disrupted input functional activation in slightly damaged processing channels and has been demonstrated between fron- units in the brain. tal and temporal brain regions in AD patients The observation that even in normal (Grady et al., 2001). areas are underactivated in some conditions (e.g. Logan et al., 2002) seems, at first glance, not to conform to the proposed model. According to our 5. Discussion model, these slight impairments of processing effi- ciency should lead to compensatory overactivation Our integrative model applies to the functional rather than underactivation of the PU. However, activation studies of both healthy aging and dementia assuming that even slight damage to grey and parti- and its precursors. Proposed models are being dis- cularly white matter leads to impaired coordination cussed for other neuropsychiatric disorders with a of the processing network, functional activation will neurodegenerative component, particularly schizo- not be distributed in the most efficient way, and the phrenia (Manoach, 2003). Progressive impairment most specialized area for a certain task might not of synaptic transmission (e.g., by synapse loss) has become fully engaged. This would result in under- been proposed to be a crucial factor in both age- activation of PU and overactivation of less specific related and dementia-related cognitive decline, with areas. However, these effects might potentially also synaptic decay being much more accelerated in be caused by methodological issues that will be dementia than in normal aging (Terry and Katzman, discussed in more detail. 2001). The results of the functional activation studies reviewed in this article show that damage to cortical 5.1. Neurovascular coupling systems – independently of its cause – may lead to changes of functional activation, which seem to fol- An important question that is not answered by our low similar rules in aging and dementia. Reduction (or any of the previous) models is whether the cou- D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 107 pling between the measured parameters (blood flow, vation studies. These include the performance of sim- BOLD-signal change, glucose consumption) and ple sensorimotor tasks in addition to cognitive tasks or actual neuronal activity is preserved in the degenera- the analysis of group-by-task interactions rather than tive brain. For a valid comparison of functional ima- main group differences (D’Esposito et al., 2003). ging results of young, older and demented subjects, However, even when activation differences (e.g., in we will ultimately have to show that vascular and primary motor cortex) might be related to changes in metabolic parameters correctly reflect neuronal activ- neurovascular coupling, this might not necessarily ity in all these groups. There is some evidence that the apply to other brain regions (e.g., in association coupling between neural activity and hemodynamic areas), at least not to the same degree. Even the response may be altered by age, cerebrovascular pro- calculation of activation differences between different cesses, drug intake and neurodegenerative diseases, cognitive tasks or between different difficulty levels and all of these factors might account for activation of a parametric task does not completely control for deficits in elderly people and dementia patients (Ross different hemodynamic response functions (HRF) in et al., 1997; D’Esposito et al., 1999; for review, see different populations because such HRF differences D’Esposito et al., 2003). For example, age-related could have a non-linear relation to neuronal activation changes of the microvasculature may alter the respon- in different tasks. Thus, although very important, such siveness of cerebral arterioles to metabolic changes measures are unfortunately not magic bullets that can (vascular reactivity) or to neuronal activity (decou- completely solve the problem of different HRF pling). Elderly participants have indeed shown response functions in different populations. It is there- reduced resting state cerebral blood flow (Bentourkia fore advisable to control for vascular risk factors et al., 2000), impaired vascular reactivity to hypercap- (, ) and already present (cerebro)- nia (Ito et al., 2002) and reduced BOLD-signal change vascular changes (e.g. arteriosclerosis, cortical infarc- during sensory or simple motor tasks (see above, tions, white matter lesions) and to exclude such Section 2). Furthermore, chronic cerebral ischemia subjects from functional activation studies on healthy can lead to secondary poststenotic vasodilatation, aging or AD (D’Esposito et al., 2003). which will reduce the difference in rCBF between Nonetheless, even if neurovascular decoupling resting and activated states and thus decrease the might be a confound in healthy elderly participants amount of functional activation changes (Derdeyn et and dementia patients, it cannot explain the wide- al., 1999). The intake of non-steroidal anti-inflamma- spread occurrence of task-related overactivations in tory drugs (NSAIDs), which is prevalent in the these groups. Although many elements of the elderly, reduces the production and the release of dynamics of cortical activation are not fully under- eicosanoids from astrocytes, which in turn may sig- stood, the functional activation studies of the aging nificantly reduce vasodilatation and reactive increases brain conducted so far permitted the in vivo observa- in rCBF (Zonta et al., 2003). Finally, glutamate and tion of the physiological effects of the brain’s efforts acetylcholine have been found to increase CBF in to counteract its progressive destruction. different brain regions and pathological changes in these neurotransmitter systems (e.g., the loss of cho- 5.2. The question of the bbaselineQ linergic neurons in AD) may additionally impair the neurovascular response (Vaucher and Hamel, 1995; In the functional imaging literature, brain activa- Zonta et al., 2003) in degenerative brain diseases. It is tion is determined as the change of the level of thus extremely difficult to attribute activation differ- activity (rCBF, BOLD-signal, metabolic changes) ences between young and old subjects or between during a task from a baseline condition. The baseline healthy subjects and patients with degenerative brain is commonly assumed to represent a bnullQ level of diseases to an altered neurovascular response or to brain activity during rest or during a control task that altered neuronal activity. is not hypothesized to change activity parameters in Some measures have been proposed to control for specific brain areas. Thus, the amount of task- the influence of (potentially) different hemodynamic induced activation in the brain is inevitably related response functions between groups in functional acti- to the baseline level. However, recent findings and 108 D. Prvulovic et al. / Psychiatry Research: Neuroimaging 140 (2005) 97–113 debates have indicated that this approach must be ences between control and patient groups. Not con- considered with caution (Stark and Squire, 2001), trolling for these factors in the experimental design or perhaps even more so in functional activation studies analysis may lead to systematic errors when compar- of dementia. ing the signals of the patient group with controls. In healthy participants, functional networks of Fortunately, some of these factors can be explicitly sensory and motor areas, as well as frontal and par- considered and quantified. ietal areas, are detectable during the resting condition (Van de Ven et al., 2004). The contribution of brain 5.3. Performance measurements areas to these networks might change with different pathological states (e.g., Malaspina et al., 2004), Without the adequate measurement of response thereby potentially contributing to the observed dif- accuracy and latency in cognitive tasks, it is difficult ferences in activation patterns across groups during to know whether an activation difference between task performance. patients and controls is caused by worse performance Some brain areas show high intrinsic activation or non-compliance in the patients. Thus, performance during the rest condition, in comparison to other measurements are necessary in order to attribute func- brain areas, and become deactivated during various tional activation differences to the disease, to differ- cognitive tasks. These include the medial parietal ences in performance, or to lack of cooperation. The cortex (precuneus and posterior cingulate), the medial use of event-related fMRI allows investigators to frontal cortex, and the bilateral inferior parietal cortex measure functional activation separately for task (see Shulman et al., 1997). These areas have been items that have been processed accurately and for suggested to constitute a bdefault modeQ network that those that have not. This approach can greatly help is more active during rest (i.e., not performing any to distinguish between functional activation differ- task) and that becomes deactivated with increasing ences that are due to physiological dysfunction, per- cognitive task demand (Raichle et al., 2001). The formance deficits, or both. physiological role of this network has not yet been resolved, but it has been associated with binner 5.4. Atrophy correction thinkingQ and monitoring of both mental and environ- mental processes (Raichle et al., 2001; McKiernan et Especially when using functional imaging techni- al., 2003). In AD patients, this bdefault modeQ net- ques with lower spatial resolution (PET, SPET), the work has been found to be less active during rest measured activation signals have been found to be when compared with healthy age-matched controls confounded by atrophy (partial volume effect) (Minoshima et al., 1997; Johnson et al., 1998; Grei- (Bokde et al., 2001). Because atrophy is generally cius et al., 2004). Furthermore, in an active semantic higher in AD than in normal aging, this is a sys- task, healthy AD patients showed less task-related tematic effect that can lead to artificially low activa- deactivation in the posterior cingulate cortex when tion signals in AD. It is therefore useful to control compared with age-matched control subjects and for the impact of local atrophy on brain activation healthy young controls (Lustig et al., 2003). This differences especially in brain regions with high finding may be explained by impaired suppression atrophy (Dickerson et al., 2004; Prvulovic et al., of competing processes during cognitive processing, 2002). by a decreased baseline activity, or both. When com- paring task-related functional activation between AD 5.5. 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