Running head: OLFACTORY AND HIGHER CORTICAL FUNCTIONS. Association between Olfactory and Higher Cortical Functions in Alzheimer s disease

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1 Running head: OLFACTORY AND HIGHER CORTICAL FUNCTIONS Association between Olfactory and Higher Cortical Functions in Alzheimer s disease Alzheimer s Disease (AD) is a disease that affects many areas of functioning. The symptoms include a gradual onset, with primarily deficits in memory, as well as concentration and language. These changes are caused by anatomical changes in the brain, which include the collection of tangles and plaques. The tangles begin in a region near the hippocampus in the temporal lobe, and spread outwards. Cognitive and anatomical changes also occur in a normal elderly population, but this decline is not as severe as in AD. Deficits related to AD that are less understood are those in olfactory functioning. Olfactory dysfunction occurs in the elderly population along with deficits in other areas of cognitive functioning. These olfactory deficits have been found to be stronger and more prevalent among Alzheimer s patients (Royall, Chiodo, Polk, & Jaramillo, 2002). Exploration of these smell deficits in AD may provide evidence of decline of neural functioning specific to this disease. This article provides evidence for the importance of exploration of olfactory functioning in AD because of possible associations between olfaction and higher-cortical functioning. Olfactory Neuroanatomy To understand the implication of olfaction in Alzheimer s disease, it is important to understand the neuroanatomy of olfaction. An odorant enters the nasal pathway and passes through the epithelium, which contains bipolar cells that detect the odor. It crosses the cribiform plate and travels to the olfactory bulbs. The olfactory bulbs contain glomeruli which encode smell information and send it along the olfactory tract. The olfactory tract divides into lateral and medial olfactory straie. Information from the lateral olfactory striae is sent directly to the primary olfactory cortex (also called the piriform cortex) in the inferior fronto-temporal junction. 1

2 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 2 Olfaction is different than other sensory functions because this information is sent directly to the cerebral cortex, while other information from the remaining senses is first sent to the thalamus. Projections from the primary olfactory cortex are then sent to several secondary and proximal neural regions, including both the orbitofrontal cortex (OFC) and the anterior medial temporal lobe (AMTL; including the structures of the hippocampus and amygdala). However, it is important to note that these regions are also important for higher cortical functioning, such as emotional memory and decision-making. Orbitofrontal cortex and decision-making The OFC is located in the ventral portion of the prefrontal cortex proximal to the temporal lobe. The OFC has been shown to have a crucial role in value-based decision-making, especially assigning the value of reward. This has been established through many brain imaging studies, as well as lesion studies. Fellows and Farah (2007) used the Iowa Gambling Task to test individuals with OFC lesions and found inconsistency in responses from these participants. Through these studies, the OFC has been shown to be essential in decision-making. Anterior medial temporal lobe and emotional memory The AMTL includes structures essential in emotional memory, such as the hippocampus and amygdala. Emotional memory includes retrieval of previously experienced or presented emotionally-valenced stimuli. Emotional information has been shown to be remembered better than non-emotional information in a normal functioning population. When there is damage to these emotional memory regions, impaired emotional memory is a result. For example, impaired emotional memory was discovered after unilateral lesions to the amygdala (Adolphs, Tranel, Denburg, 2000). Hamann, Ely, Grafton, & Kilts, (1999) also suggested that the amygdala

3 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 3 assisted in the encoding of both pleasant or aversive emotional stimuli. In conclusion, it seems that the anterior medial temporal lobe structures are necessary when forming emotionally charged memories. Aim and Hypotheses By examining smell functioning, we may be able to evaluate functioning of these other areas of the brain due to their close proximity to each other and similar neural decline from aging and AD. Due to the progression of aging and AD in the brain, it is plausible to believe that these regions are affected similarly, though no research has explored a possible correlation between functioning of these regions. This project can reveal olfaction as a gateway to other areas of the brain. The aim of the current study is to investigate the relationship between olfactory functioning and higher cortical functions, which includes decision-making and emotional memory. It is hypothesized that olfactory functioning will be positively associated with decisionmaking and emotional memory abilities in a healthy elderly and AD population, with stronger deficits in the AD population. METHODS Subjects: Demographic information is displayed in Table 1. Eight people participated in this study. Exclusion criteria included other neurological conditions that could contribute to impairment (ie. stroke, severe head trauma, brain tumor, meningitis, encephalitis, seizure disorder, and severe migraine), intellectual disabilities, depression, other psychiatric disease, and nasal conditions that interfere with the ability to smell. Furthermore, none of the participants experienced significant symptoms of depression, as assessed by the Beck Depression Inventory. (Mean 3.38; Range 0-7). Four patients with probable Alzheimer s disease were recruited from

4 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 4 the Benton Neuropsychology Clinic from University of Iowa. Alzheimer s participants had a mean age of (Range 70-90; SD 10.72) with a mean education level of 15.5 years (SD 2.52). The four healthy elderly participants had a mean age of (Range 67-71; SD 1.89) with a mean education level of (SD 2.36). Healthy elderly were made up of one Caucasian male, and three Caucasian females. AD participants were made up of two Caucasian males, and two Caucasian females. All participants gave written consent to the protocol approved by the University of Iowa Institutional Review Board. AD participants were significantly lower compared to healthy elderly on the Montreal Cognitive Assessment (p <.05). Stimuli Olfactory tests Smell functioning was assessed using two smell tests: The University of Pennsylvania Smell Identification Test (UPSIT) and the Odor Memory Test. The Smell Identification Test is a 40-item four-alternative forced choice test with microencapsulated odorants in scratch and stiff format. It takes minutes to administer, and has a good test-retest reliability of.90 (Doty McKeown, Lee, & Shaman 1995). The Odor Memory Test is a 12-item four-alternative forced choice test with microencapsulated odorants in scratch and sniff format. The test includes the presentation of one odorant, a delay interval (10, 30 or 60s), and then the presentation of 4 odors. Participants then state which odor that was previously presented. Between the primary presentation and recognition stage, participants count backwards by 3 from 280 to lower verbal rehearsal. The test has a test-retest reliability of.68 (Doty et al., 1995). Decision making tasks

5 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 5 The decision making tasks conducted included the Iowa Gambling Task, and the Balloon Analogue Risk Task. The Iowa Gambling Task is a computer-based decision-making task involves the selection cards from four decks. The selection of a card results in a monetary reward or a monetary reward and a penalty. Participants were told that some decks are more advantageous than others, and the point of the game is to win as much money as possible. Selecting the advantageous decks result in a net gain, while the disadvantageous decks result in a net loss. The Balloon Analogue Risk Task (BART) is a computerized risk assessment task. A balloon is presented on the computer screen, with a temporary bank and a permanent bank. When participants pump of the balloon, they collect money in their temporary bank. If they push the stop button before the balloon pops, they transfer the monetary reward to their permanent bank. Participants are told that the more they pump up the balloon, the more money they can earn in the game. On the other hand, if they pop the balloon, they lose all money in their temporary bank on the screen. A new balloon appears if their balloon pops. There are 30 trials. Emotional Memory Stimuli The emotional memory stimuli were chosen from the International Affective Picture System (Lang, Bradley, & Cuthbert, 1999), which is a battery of a variety of pictures with normative ratings on valence, arousal, and dominance. 60 pictures were chosen based on the IAPS ratings of valence and arousal into three categories: 20 positive, 20 negative, and 20 neutral. Procedure Participants completed the olfactory tests, decision making tasks, and emotional memory tasks in a session that lasted approximately 4 hours. Participants first completed the emotional

6 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 6 memory recall task. The sixty pictures from the IAPS were presented twice to participants. The first time pictures were presented, participants rated each picture on a scale of valence and arousal. There was no significant difference between participants ratings and IAPS ratings. Then pictures were presented a second time without any ratings. Immediately after the two presentations of pictures, participants were given a free recall test. During the free recall task, they were told to provide a description of pictures that were previously presented. Pictures were counted as correct if the description applied exclusively to one picture. Afterwards, the participants completed a cued recall task. The task contained the seven cues: injured people, celebration, school, household objects, structures/architecture, animals, and transportation. After the conclusion of the free and cued recall, participants completed the Montreal Cognitive Assessment. This test assesses several areas of cognitive functioning, including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Afterwards, the emotion recognition task occurred. Participants were presented with 120 slides. Sixty of these pictures were slides presented at the beginning of the emotional memory task, and sixty were foils. Two pictures were presented at once, and participants were instructed to choose the picture that was presented previously. The foil pictures were matched to the initial slides based on emotion and arousal level. Afterwards, participants conducted the Odor Memory Task. Then participants completed the Iowa Gambling Task and the Balloon Analogue Risk Task. The participants then were given the Wechsler Test of Adult Reading (Wechsler, 2001). The Wechsler Test of Adult Reading was included as a control task because this task was not expected to correlate with olfactory

7 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 7 functioning. Lastly, participants were given the University of Pennsylvania Smell Identification Task. Data Analyses The Balloon Analogue Risk Task was analyzed using the adjusted number of pumps, which is the average number of pumps without exploded balloons. The Iowa Gambling Task was analyzed by subtracting the number of bad decks (A+B) from the number of good decks (C+D). The emotional memory recall and recognition score was calculated by the amount of remembered emotional pictures (average of remembered positive and negative pictures). Nonemotional memory was calculated by the amount of remembered neutral pictures. The Odor Identification Task was calculated based on correct odors identified in the 40 four-alternative multiple choice test. The Odor Memory Task was scored based on the amount correctly in the 12 four-alternative forced choice test. The Wechsler Test of Adult Reading was scored based on the raw score of words pronounced correctly. Due to non-normality of the data and small sample size, a Spearman correlation was run between each smell variable (Odor Identification, Odor Memory Task) and the decision-making/emotional memory variables for both AD and elderly. Preliminary Results Olfaction and Cognition A correlation analyses was first evaluated between the odor identification/odor memory for the Montreal Cognitive Assessment. A significant correlation was found between odor identification and the MOCA, as well as odor memory and MOCA as since in Figure 1 and Figure 2 (r =.810, p<.05; r =.934, p<.05). This supports previous research that dementia is associated with olfactory decline.

8 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 8 Olfaction and Emotional Memory A spearman correlation was analyzed between each smell variable and two emotional memory variables (emotional recall and emotional recognition). A significant relationship was found between odor memory and emotional recognition (Figure 3; r =.749, p<.05), and odor memory and emotional recall (Figure 4; r=.849, p<.05). The association between odor identification and emotional recall was significant (Figure 5; r=.735, p<.05), but no significant relationship was found between odor identification and emotional recognition (Figure 6; r=.634, p>.05). Olfaction and Non-emotional Memory After finding a significant relationship between olfaction and emotional memory, an analysis needed to be conducted between olfaction and non-emotional memory. This analysis could explain if the relationship was due to the emotional content of the stimuli, or memory in general. A significant relationship was found between odor identification/odor memory and nonemotional recall as displayed in Figure 7 and 8 (r =.843; p<.05; r =.849; p<.05). There was not a significant relationship found between odor identification/odor memory and non-emotional recognition as displayed in Figure 9 and 10 (r =.843; p>.05; r =.855; p>.05). Olfaction and Decision-making A spearman correlation was analyzed between each smell variable and decision-making variable (Iowa Gambling Task and Balloon Analogue Risk Task). No significant relationship was found between odor identification and IGT or BART (Figure 11, r =.491, p>.05; Figure 12, r =.143, p>.05). Furthermore, no significant relationship was found between odor memory and IGT or BART (Figure 13, r = -.090, p>.05; Figure 14, r =.527, p>.05).

9 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 9 Olfaction and Reading No significant relationship was found between odor identification or odor memory and the Wechsler Test of Adult Reading (Figure 15, r =.419, p>.05; Figure 16, r =.488, p>.05). Discussion In summary, an association was found between olfaction and emotional recall and nonemotional recall. This finding did not support the hypothesis, but is still informative for the use of olfaction in an elderly and Alzheimer s population. No association was found between olfaction and decision-making tasks, which did not support the hypothesis. Lastly, no association was found between olfaction and the Wechsler Test of Adult Reading, which did support the hypothesis. There are several possible reasons for the findings in this study. First of all, there was a significant relationship between olfaction and memory in general. The proximal neural connections between olfaction and memory have been established in the literature. This finding somewhat replicates findings by Djordjevic, Jones-Gotman, De Sousa, and Chertkow (2008) who found that olfaction was related to the Wechsler Memory Scale in an Alzheimer s population. However, this finding needed to be replicated with different stimuli, especially since the WMS is not very reliable within a dementia population. Secondly, a significant relationship was not found between olfaction and decision-making as expected. The reason for this finding may be because the OFC is not as affected by neural decline as the medial temporal lobe in these Alzheimer s participants. Tangles begin near the hippocampus in the temporal lobe early in the disease, and then damage spreads outward. It is understandable that olfaction and memory would

10 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 10 be compromised within this population of mild and moderate Alzheimer s participants, though the OFC may not yet be affected. Limitations There are several limitations of the current research study. The study has a small number of participants, and will be increased in the future. Furthermore, the sample is primarily Caucasian and highly educated which makes it difficult to generalize the findings. Lastly, more participants with mild cognitive impairment will be collected in the future to provide a more extensive array of cognitive and olfactory abilities. Conclusion and Future Research Investigating an association between olfaction and higher cortical functions has important implications. The relationship between smell functioning and memory could provide a standardized olfactory measurement to provide easier assessment of memory within a neuropsychology clinic. The assessment of memory can be very time consuming. Due to the positive correlation between olfaction and memory, clinicians could learn about the patient s memory functioning with a quick smell assessment. Lastly, these associations generate a better understanding of the nature of neural dysfunction in key regions known to be affected by aging and AD. Future research exploring the relationship between olfaction and the brain is essential. Future research should investigate other populations, such as Parkinson s patients and Amyloid Lateral Sclerosis patients since they also have documented olfactory impairments. Investigation of the olfactory deficits in neurological populations may find similarities in neural decline of functional networks and increase the use of olfaction in clinical settings.

11 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 11 References Adolphs, R., Tranel, D., & Denburg, N. (2000). Impaired Emotional Declarative Memory Following Unilateral Amygdala Damage. Learning & Memory, 7(3), Djordjevic, J., Jones-Gotman, M., De Sousa, K., & Chertkow, H. (2008). Olfaction in patients with mild cognitive impairment and Alzheimer s disease. Neurobiology of Aging, 29, Doty, R.L., McKeown, D.A., Lee, W.W., & Shaman, P. (1995). A study of the test-retest reliability of ten olfactory tests. Chemical Senses, 20(6), Fellows, L. K., & Farah, M. J. (2007). The role of ventromedial prefrontal cortex in decision making: Judgment under uncertainty or judgment perse? Cerebral Cortex, 17, Hamann, S.B., Ely, T.D., Grafton, S.T., & Kilts, C.D. (1999). Amygdala activity related to enhanced memory for pleasant and aversive stimuli. Nature Neuroscience, 2, Lang, P.J., Bradley, M.M., & Cuthbert, B.N.(1999). The international affective picture system (IAPS): Technical manual and affective ratings. Gainesville, FL: University of Floria, The Center for Research in Psychophysiology. Royall, D.R., Chiodo, L.K., Polk, M.J., & Jaramillo, C.J. (2002). Severe Dysosmia is specifically associated with Alzheimer-like memory deficits in nondemented elderly retirees. Neuroepidemiology, 21, Wechsler, D. (2001). Wechsler Test of Adult Reading. San Antonio, TX: Psychological Corporation.

12 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 12 Figure and Tables Table 1 Groups Gender Age Education MOCA Alzheimer s (n=4) 2 Female 2 Male Mean SD Range Normal Elderly (n=4) 3 Female 1 Male Mean SD Figure 1 Range Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

13 OLFACTORY AND HIGHER CORTICAL FUNCTIONS 13 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16