**3. Tactile angle cognitive ability for distinguishing normal aging and dementia**

#### **3.1 Introduction**

As described above, AD is a progressive neurodegenerative disease that is characterised by a loss of neurons and synapses in the cerebral cortex. Currently, many pathophysiological and molecular neurological studies (Francis et al., 1999) have focused on the cause of AD to find its clinical biomarkers, such as phosphorylated tau. In recent decades, researchers have also used PET (Huang et al., 2010) and fMRI (Delbeuck et al., 2003; Johnson et al., 2006) to assess brain functional deficits and disconnections between cerebral areas in patients with mild cognitive impairment (MCI) and AD. These studies have shown that AD brains may have different activity and connectivity patterns compared to normal brains. A few recent neuropsychological studies (Baddeley et al., 1991) have also explored the effects of disconnection between cerebral areas on cognitive functioning.

The altered cognitive symptoms in the earliest stages of AD include mild problems in learning, memory and planning (Förstl & Kurz, 1999). Unlike normally aged controls, profound impairments in working memory, episodic memory and spatial discrimination are found in patients with AD (McKhann et al., 1984). Eventually, most AD patients in the severe stages of the disease lose their ability to perform the simplest of tasks encountered in their daily routine. Mild cognitive impairment is a clinical disorder that afflicts elderly individuals and is characterised by memory impairment that does not interfere significantly with their daily living (Petersen et al., 1999). In addition, MCI is a major risk factor in the development of AD (Petersen, 2004). Currently, the mini-mental state examination (MMSE) (Folstein et al., 1975) and the clinical dementia rating (CDR) system (Morris, 1993) are used as references to help a physician determine whether a person diagnosed with memory problems has AD.

The somatosensory system is a diverse sensory system comprising the receptors and processing centres to produce the sensory modalities. Tactile spatial discrimination is one of the major manual learning and memory skills of humans. Tactile spatial acuity at the fingertips varies significantly with age (Stevens & Patterson, 1995). Previous studies have suggested two possible effects of this variation on tactile spatial discrimination: (a) differences in the central pathways of the brain leading to tactile perception and (b) differences in afferent innervation density between younger and older subjects. However, the differences in the ability to discriminate tactile angles between healthy older individuals and patients with MCI and AD has not been reported.

To differentiate two different objects by touch, humans need to store the spatial information of the first object in their working memory and then compare the spatial construction of the first object to that of the second. This procedure activates a diverse cerebral network that primarily includes areas involved with the initial processing of skin indentations (i.e., primary and secondary somatosensory cortex) (Blatow et al., 2007), the high-class areas for computation and elaborate reconstruction of shapes (i.e., part of the intraparietal sulcus) and the prefrontal cortex (Bodegård et al., 2001), which is activated for tactile working memory processing. We hypothesise that having abnormal somatosensory information processing contributes to the functional decline of tactile shape discrimination in patients with MCI and AD compared to NC individuals.

In this section from our recent study (Yang et al., 2010), we characterised tactile shape discrimination deficits in patients with MCI and AD and assessed whether tactile shape discrimination impairment could distinguish patients with MCI and AD from NC individuals. To allow a controlled study of shape, we used a restricted working definition of shape that can be applied to any object with angles (Wu et al., 2010) and to examine the ability to identify differences in raised angles in MCI and AD patients and the NC individuals. The results indicated that the decline in tactile angle discrimination in patients with MCI and AD compared to the NC group was significant.

#### **3.2 Methods**

44 Neuroimaging for Clinicians – Combining Research and Practice

the activation that resulted from spatial or temporal cues. The activation in VS–VN in the frontal (BA4/6/47) and parietal (BA7/40) cortices was similar to previous studies (Coull & Nobre, 1998; Nobre et al., 2000). The VT–VN revealed bilateral activation in the parietal

The right hemisphere bias for spatial orientation in this study was consistent with a previous report (Coull & Nobre, 1998). Therefore, we conclude that visual orienting attention uses a frontal–parietal neutral network for visual spatial orienting attention but

We used a visual cue in the auditory orienting attention tasks, whereas no cue was used in previous studies (Zatorre et al., 1999; Degerman et al., 2006). When comparing the activation in those studies, we found common areas in both the parietal (BA7) and frontal (BA6) cortices. In this study, the prefrontal cortex showed less activation than in previous studies (Zatorre et al., 1999; Degerman et al., 2006), and when examining the RT in the auditory orienting attention task that revealed a slow reaction, we noted that the magnetic resonance machine made a sound that drew the subjects' attention. Therefore, the AT–AN showed no activation for the same problem. One study (Schubotz et al., 2003) mentioned an auditory temporal attention task, with activation of the inferior temporal gyrus (BA20) and fusiform gyrus (BA37). In that study, only one temporal interval was used, which was different than

Some studies (Loose et al., 2003; Johnson & Zatorre, 2006) used both visual and auditory stimuli to measure the attention to the stimuli feature and divided attention. Although no spatial or temporal attention task was applied using a similar task, they revealed similarities between the activation in response to visual and auditory tasks. We postulate that if the proper auditory stimulus was used in the auditory orienting attention task, neutral network

As described above, AD is a progressive neurodegenerative disease that is characterised by a loss of neurons and synapses in the cerebral cortex. Currently, many pathophysiological and molecular neurological studies (Francis et al., 1999) have focused on the cause of AD to find its clinical biomarkers, such as phosphorylated tau. In recent decades, researchers have also used PET (Huang et al., 2010) and fMRI (Delbeuck et al., 2003; Johnson et al., 2006) to assess brain functional deficits and disconnections between cerebral areas in patients with mild cognitive impairment (MCI) and AD. These studies have shown that AD brains may have different activity and connectivity patterns compared to normal brains. A few recent neuropsychological studies (Baddeley et al., 1991) have also explored the effects of

The altered cognitive symptoms in the earliest stages of AD include mild problems in learning, memory and planning (Förstl & Kurz, 1999). Unlike normally aged controls, profound impairments in working memory, episodic memory and spatial discrimination are found in patients with AD (McKhann et al., 1984). Eventually, most AD patients in the

cortex (BA7) (Coull et al., 2000).

this study.

**dementia** 

**3.1 Introduction** 

uses the parietal cortex for visual temporal attention.

**2.4.2 The cue used in the auditory orienting attention task** 

activation and visual orienting attention might be demonstrated.

disconnection between cerebral areas on cognitive functioning.

**3. Tactile angle cognitive ability for distinguishing normal aging and** 

#### **3.2.1 Subjects**

Three groups of right-handed subjects (i.e., NC, MCI and AD) consented to participate in the study. Handedness was confirmed with the Edinburgh Handedness Inventory (EHI) (Oldfield, 1971). All MCI and AD patients were recruited from the Okayama University Hospital, Japan, and all subjects had no deficits in motor and sensory systems and deep tendon reflexes. They also reported no loss of tactile sensation or any unusual experiences with haptic input. All subjects signed informed consent forms, and the experiments were performed in accordance with a protocol approved by the Okayama University.

Early Detection of Alzheimer's Disease with Cognitive Neuroscience Methods 47

Fig. 6. Example of angle stimuli and position of subject's finger. (a) An illustration of the reference angle (60°) and two of eight comparison angles (64° and 110°) used in this experiment. (b) Three-dimensional view of an example of angle. (c) The angle movement apparatus and the subject's finger position. The reference angle and one comparison angle of a typical trial were clamped on the apparatus. These angles were moved by an electric slide on the tactile apparatus from right to left in a horizontal direction. The subject's right

We measured angle discrimination thresholds based on each subject's ability to judge the relative sizes of the reference angle and the comparison angles. All subjects were asked to place their right index fingers at the initial starting point of the plate (Fig. 6(c)). To hold the right index finger and arm in the vertical direction, the right hand was fixed to the plate, and the forearm was fixed to an immobile support stand. The subjects wore an eye mask during the task to prevent visual feedback. Moreover, all subjects were asked to keep their right hand immobile and perceive the angles passively. For AD patients, the experimenter intermittently reminded the patients of this requirement to ensure compliance with the

As shown in Fig. 6(c), the experimenter first clamped the reference angle and one of eight comparison angles on the apparatus. Then, the angles were moved under the subject's right index finger for the subject to perceive the size of the angle by following the imaginary bisector. Moreover, all angles were moved from the end points towards the apex. Each angle was scanned in succession, once per trial. The contact force was restricted, and the movement speed of the angles was maintained at 5.0 mm/s. The subject was then asked to verbally identify the larger angle in each pair of angles (2AFC: two-alternative forced choice). A pseudorandom order was used to present the reference angle and comparison angle to the subject. The reference angle was either the first or the second angle in each pair presented to the subjects who were not informed about the change in the order of angles.

hand was fixed on the plate and kept static during each discrimination trial.

instructions to differentiate the size of the two angles.

**3.2.3 Procedure** 

The NC group consisted of 14 subjects between the ages of 67 and 79, with a mean age of 71.5±3.7 years. The NC individuals were designated as "cognitively normal" when they presented no cognitively based limitations in daily living activities, and the NC was defined by an MMSE score (Folstein et al., 1975) of 27 or greater and a CDR (Hughes et al., 1982) of 0. No NC subjects had a history of neurological or psychiatric disease, and no subjects were taking any medications that affected the central nervous system at the time of testing.

The MCI group consisted of 10 subjects between the ages of 56 and 85, with a mean age of 71.3±9.4 years. Patients with amnestic MCI were diagnosed using the Petersen criteria (Petersen et al., 1999). In addition, all patients with amnestic MCI had MMSE scores of 27 or greater and CDR scale scores of 0.5. These individuals underwent magnetic resonance imaging (MRI) of the brain to confirm that they did not have a focal lesion that affected memory sensitive substrates. As assessed by the Consortium to Establish a Registry for Alzheimer's Disease cognitive battery (Morris et al., 1989), MCI patients typically show a memory performance that was 1.5 reference deviations below the age-adjusted average, which includes verbal learning, recognition and recall tests, global cognitive function and activities of daily living impairment.

The AD group consisted of 13 subjects between the ages of 57 and 83, with a mean age of 73.4±7.7 years. The diagnosis of AD was made in accordance with the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Alzheimer's Disease and Related Disorders Association (ADRDA) criteria (Morris et al., 1989). All patients with AD had MMSE scores between 15 and 26 and a CDR score of 1 or 2, corresponding to what is known as mild to moderate AD.

In addition, all MCI and AD patients were confirmed based on a Rosen modified Hachinski ischemic score that was at least 4 (Rosen et al., 1980), and they did not show any atrophy of the somatosensory cortex on MRI. Patients were excluded if they had clinically significant neurological diseases other than MCI and AD or had a major psychiatric disorder. Psychiatric co-morbidity was excluded by history, clinical examination, and a Composite International Diagnostic Interview (Robins et al., 1988).

#### **3.2.2 Apparatus and stimuli**

One reference angle and eight comparison angles were used in this study. During each trial, one pair of angles consisting of the reference angle, and a comparison angle was presented to the subject. Fig. 6(a) is an illustration of the angles. In this experiment, the apex of the angles was always pointing to the right. All angles were mounted so the two arms were symmetrically placed above and below an imaginary bisector. The size of the reference angle was 60° with the eight comparison angles being larger than the reference angle by 4°, 8°, 12°, 16°, 20°, 24°, 32° and 50°. The raised angles consisted of custom-built plastic shapes that were raised 0.5 mm (Fig. 6(b)) over a 40.0 mm square base. Varying in two spatial dimensions, the angles were formed by two raised lines (i.e., the arms of the angles) at the centre of the 40.0 mm square base with an accuracy of ± 0.1°. The arms were 8.0 mm long and 1.5 mm wide.

As shown in Fig. 6(c), the two angles were clamped horizontally in the apparatus. Subjects were blindfolded and seated at a table. The right hand of the subject was fixed with tape to an immobile plastic plate with only the right index finger making contact with the angles. The apparatus consisted of an electric slide that moved the angles along the horizontal axis in the transverse plane.

Fig. 6. Example of angle stimuli and position of subject's finger. (a) An illustration of the reference angle (60°) and two of eight comparison angles (64° and 110°) used in this experiment. (b) Three-dimensional view of an example of angle. (c) The angle movement apparatus and the subject's finger position. The reference angle and one comparison angle of a typical trial were clamped on the apparatus. These angles were moved by an electric slide on the tactile apparatus from right to left in a horizontal direction. The subject's right hand was fixed on the plate and kept static during each discrimination trial.

#### **3.2.3 Procedure**

46 Neuroimaging for Clinicians – Combining Research and Practice

The NC group consisted of 14 subjects between the ages of 67 and 79, with a mean age of 71.5±3.7 years. The NC individuals were designated as "cognitively normal" when they presented no cognitively based limitations in daily living activities, and the NC was defined by an MMSE score (Folstein et al., 1975) of 27 or greater and a CDR (Hughes et al., 1982) of 0. No NC subjects had a history of neurological or psychiatric disease, and no subjects were taking any medications that affected the central nervous system at the time of testing.

The MCI group consisted of 10 subjects between the ages of 56 and 85, with a mean age of 71.3±9.4 years. Patients with amnestic MCI were diagnosed using the Petersen criteria (Petersen et al., 1999). In addition, all patients with amnestic MCI had MMSE scores of 27 or greater and CDR scale scores of 0.5. These individuals underwent magnetic resonance imaging (MRI) of the brain to confirm that they did not have a focal lesion that affected memory sensitive substrates. As assessed by the Consortium to Establish a Registry for Alzheimer's Disease cognitive battery (Morris et al., 1989), MCI patients typically show a memory performance that was 1.5 reference deviations below the age-adjusted average, which includes verbal learning, recognition and recall tests, global cognitive function and

The AD group consisted of 13 subjects between the ages of 57 and 83, with a mean age of 73.4±7.7 years. The diagnosis of AD was made in accordance with the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) Alzheimer's Disease and Related Disorders Association (ADRDA) criteria (Morris et al., 1989). All patients with AD had MMSE scores between 15 and 26 and a CDR score of 1 or 2, corresponding to what is

In addition, all MCI and AD patients were confirmed based on a Rosen modified Hachinski ischemic score that was at least 4 (Rosen et al., 1980), and they did not show any atrophy of the somatosensory cortex on MRI. Patients were excluded if they had clinically significant neurological diseases other than MCI and AD or had a major psychiatric disorder. Psychiatric co-morbidity was excluded by history, clinical examination, and a Composite

One reference angle and eight comparison angles were used in this study. During each trial, one pair of angles consisting of the reference angle, and a comparison angle was presented to the subject. Fig. 6(a) is an illustration of the angles. In this experiment, the apex of the angles was always pointing to the right. All angles were mounted so the two arms were symmetrically placed above and below an imaginary bisector. The size of the reference angle was 60° with the eight comparison angles being larger than the reference angle by 4°, 8°, 12°, 16°, 20°, 24°, 32° and 50°. The raised angles consisted of custom-built plastic shapes that were raised 0.5 mm (Fig. 6(b)) over a 40.0 mm square base. Varying in two spatial dimensions, the angles were formed by two raised lines (i.e., the arms of the angles) at the centre of the 40.0 mm square base with an accuracy of ± 0.1°. The arms were 8.0 mm long

As shown in Fig. 6(c), the two angles were clamped horizontally in the apparatus. Subjects were blindfolded and seated at a table. The right hand of the subject was fixed with tape to an immobile plastic plate with only the right index finger making contact with the angles. The apparatus consisted of an electric slide that moved the angles along the horizontal axis

activities of daily living impairment.

known as mild to moderate AD.

**3.2.2 Apparatus and stimuli** 

and 1.5 mm wide.

in the transverse plane.

International Diagnostic Interview (Robins et al., 1988).

We measured angle discrimination thresholds based on each subject's ability to judge the relative sizes of the reference angle and the comparison angles. All subjects were asked to place their right index fingers at the initial starting point of the plate (Fig. 6(c)). To hold the right index finger and arm in the vertical direction, the right hand was fixed to the plate, and the forearm was fixed to an immobile support stand. The subjects wore an eye mask during the task to prevent visual feedback. Moreover, all subjects were asked to keep their right hand immobile and perceive the angles passively. For AD patients, the experimenter intermittently reminded the patients of this requirement to ensure compliance with the instructions to differentiate the size of the two angles.

As shown in Fig. 6(c), the experimenter first clamped the reference angle and one of eight comparison angles on the apparatus. Then, the angles were moved under the subject's right index finger for the subject to perceive the size of the angle by following the imaginary bisector. Moreover, all angles were moved from the end points towards the apex. Each angle was scanned in succession, once per trial. The contact force was restricted, and the movement speed of the angles was maintained at 5.0 mm/s. The subject was then asked to verbally identify the larger angle in each pair of angles (2AFC: two-alternative forced choice). A pseudorandom order was used to present the reference angle and comparison angle to the subject. The reference angle was either the first or the second angle in each pair presented to the subjects who were not informed about the change in the order of angles.

Early Detection of Alzheimer's Disease with Cognitive Neuroscience Methods 49

significant r2 values of 0.98, 0.98, and 0.67 for the NC, MCI and AD groups, respectively [NC: F(1,6) = 323.95, P < 0.001; MCI: F(1,6) = 473.76, P < 0.001; AD: F(1,6) = 12.16, P = 0.013]. The mean angle discrimination accuracy for the NC (82.1% ± 2.2%), MCI (78.6% ± 1.8%) and AD (67.9% ± 2.5%) groups is shown in Fig. 8(a). We performed a one-way ANOVA on the mean accuracy. The mean accuracy of the angle discrimination differed significantly between the three groups [F(2,34) = 8.01, P = 0.001]. A multiple comparison using the Bonferroni correction (α = 0.05) revealed that the mean accuracy of patients with AD was significantly lower than patients with MCI (P = 0.04) and the NC subjects (P = 0.001). However, the difference in accuracy between patients with MCI and NC subjects was not

Fig. 7. Calculation method of the angle discrimination threshold. Accuracy of one NC subject is plotted as a function of the angular difference between the comparison (62°–110°) and the reference angle (60°). The solid line represents the logistic curve for threshold calculation. The horizontal dashed line indicates accuracy at 75%. The horizontal axis value

To examine whether the patients with MCI and AD showed any decline in angle discrimination, we further examined the angle discrimination threshold. We performed a one-way ANOVA and a multiple comparison using the Bonferroni correction (α = 0.05) on the mean discrimination threshold. As shown in Fig. 8(b), differences in the mean discrimination thresholds among patients with AD (25.2°±4.2°) or MCI (13.8°±2.7°) and NC subjects (8.7±0.8°) were significant [F(2,34) = 9.45, P < 0.001], with a larger threshold in patients with AD compared to patients with MCI (P = 0.036) and NC (P < 0.001). In addition, the threshold in patients with MCI was also significantly larger compared to NC (P = 0.049). These results indicated that the decline in the ability to discriminate tactile angles in patients

of the intersection between the 75% line and logistic curve is defined as the angle

discrimination threshold. For this NC subject, the threshold is 10.7°.

with MCI and AD was significant compared to the NC group.

significant (P = 0.93).

Each subject underwent at least 10 practice trials prior to the start of the experiment. After the training, each pair of angles was presented 10 times in a pseudorandom order. Each subject completed 80 angle discrimination trials.

#### **3.2.4 Data processing and analysis**

In this study, the 2AFC technique was used to measure the angle discrimination threshold. Subjects were forced to make a choice of what they perceived was the larger of two angles even if they could not detect a difference. The logistic curve is the most common sigmoid curve used extensively in cognitive psychological experiments for measuring thresholds (Voisin et al., 2002a,b). Here, the accuracy data were applied to the following logistic function (1) (adapted from Wu et al., 2010):

$$Accuracy = \frac{1}{1 + e^{d[\text{RA} - \text{CA}]}} \tag{1}$$

In this equation, *d* represents the unique degree of freedom of the logistic curve, which was adjusted to fit the accuracy data. *RA* and *CA* represent the degree values of the reference and comparison angles, respectively.

The discrimination threshold was defined as the angle difference at an accuracy rate of 75%. Fig. 7 shows the 2AFC results of one NC subject. The discrimination threshold is indicated where the accuracy line and the 75% line (dashed line) intersect. The discrimination threshold (DT) was computed from the logistic function (2) as follows (X = 75% accuracy):

$$DT = d^{-1}Ln(\frac{1-X}{X})\tag{2}$$

The data were incorporated into logistic functions (1) and (2). The same analyses were applied to all of the data in this experiment.

#### **3.2.5 Statistics**

To calculate angle discrimination thresholds, regression analysis with logistic function was performed. Differences in the accuracy and discrimination thresholds of the three subject groups were analysed using separate one-way analysis of variance (ANOVA). The level of significance was fixed at P < 0.05. The Bonferroni test (α = 0.05) was performed to detect the difference between each subject group. Finally, to compare the sensitivity of angle discrimination accuracy and the MMSE score, a receiver operator characteristic (ROC) analysis was used. All analyses were performed using SPSS version 12.0j (SPSS, Tokyo, Japan).
