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Benito Damasceno

Research
on Cognition
Disorders
Theoretical and Methodological Issues
Research on Cognition Disorders
Benito Damasceno

Research on Cognition
Disorders
Theoretical and Methodological Issues
Benito Damasceno
Department of Neurology
State University of Campinas (UNICAMP)
Campinas, São Paulo, Brazil

ISBN 978-3-030-57265-5    ISBN 978-3-030-57267-9 (eBook)


https://doi.org/10.1007/978-3-030-57267-9

© Springer Nature Switzerland AG 2020


This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To my wife Dione, my sons Eduardo and
Alfredo, and my uncle Eduardo who raised
me with love and wisdom.
Preface

This book is addressed to all those interested in studying the human mind, espe-
cially in doing research on disorders of cognition, being intended for graduate and
postgraduate students (in projects of scientific initiation, master’s and PhD theses)
as well as for postdoctoral researchers in the areas of neurology, cognitive neurosci-
ence, psychology, neuropsychology, psychiatry, education, and linguistics. It is the
result of my theoretical and practical experience in teaching and researching in neu-
rology, neuropsychology, and cognitive neuroscience at the State University of
Campinas (UNICAMP, Brazil) since 1986. The focus is on theoretical-methodolog-
ical issues, controversies, and limitations of current studies in cognition disorders.
Part I is about cognitive functions and their interrelationships. Functions such as
perception, attention, visuospatial-motor abilities, memory, language, and intellec-
tual reasoning are conceived, not as isolated mental “faculties,” a priori existing, or
as “modules” located in restricted brain center, but as complex functional systems
which represent the world by means of signs (mainly those of language), result from
the appropriation (internalization) of external actions and relations of the individual
with other persons and things, and have a cerebral organization distributed in vari-
ous interconnected regions. Theoretically, several studies conceive the cognitive
functions as neurofunctional networks, but in the methodological implementation
of their research they do not consider them as functional systems, with each func-
tion being reciprocally influenced by others, particularly by those most relevant for
the execution of the proposed test or task.
Part II deals with the historical-cultural origin of cognition, presenting its phylo-
genetic and ontogenetic development, from perception to theory of mind, social
cognition, language, and intellectual reasoning. A problem with various studies is
their exclusively biological or computational approach to the human mind.
Obviously, our mind is the product of a long biological evolution, besides being
mediated by biological, neurophysiological, and neurochemical processes.
Computations also underlie the mental functioning and have even been imple-
mented in electronic neural networks, helping us to better understand, for example,
visual perception. Notwithstanding, the human mind is an emergent property of
these processes and cannot be reduced to them; it is the interface between the organ-

vii
viii Preface

ism and the world, being mediated by signs, particularly those of language, and
therefore by internalized social-cultural elements acquired in joint social practice,
and whose lack or deprivation in the critical periods of the mental-cerebral develop-
ment impairs the acquisition of a normal mind. In addition to the biological and
computational processes, the mental act of the human being also involves subjectiv-
ity, free will, and the social regulation of attitudes and decision making.
Part III addresses methodological issues of the neuropsychological investigation
of patients with brain disease, focusing on brain-behavior correlations, especially
on detection of impaired basic mental mechanisms or operations and, in this way,
drawing inferences about the regional distribution of the brain lesion or dysfunc-
tion. Based on the systemic approach, the neuropsychological battery has to include
appropriate tests for the function being studied, including control tests (counter-
proofs) and control conditions, particularly the comparison with healthy matched
subjects. For example, performance in a test of learning and delayed recall of a list
of words may be affected by impairment of other functions such as attention, verbal
fluency, motivation (apathy), and humor state (depression). Thus, for knowing
whether the low scores in this test are due to a primary impairment of episodic
memory (and, by inference, to a hippocampal lesion) or due to a disturbance of
other mental functions (e.g., attention, verbal fluency, humor state), we need control
tests (counter-proofs) for these other functions. The influence of these variables
(mainly subject variables such as age and education) should be foreseen in the plan-
ning phase of the project, or should be verified after data collection by means of a
multivariate analysis. So, it is emphasized to use appropriate study designs as well
as randomization and matching for controlling subject variables which could, other-
wise, confound the results of the investigation.
Part IV presents the fundamentals of descriptive and inferential statistics applied
to biomedical and psychological research. The four chapters in this part cover defi-
nitions of basic concepts, elements of statistical analysis, hypothesis testing, and
choice of tests. The intention is to make the science of statistics more interesting and
easier to be understood even by graduate students. With this purpose, practical illus-
trations are given about how to calculate Z score, effect size, chi-squared (χ2) test,
t-test, Pearson´s correlation coefficient (r), and simple linear regression. Obviously,
these tests can be immediately run by online calculators of free software programs,
but the idea here is to teach the student the rationale behind such tests.
Part V deals with methodological issues in cognition research on three selected
conditions: multiple sclerosis, temporal lobe epilepsy, and Alzheimer’s dementia.
Why these conditions and not others? I chose them because they have been the
objects of my neurological practice, teachings, and researches, including clinical
trials, since I started as professor at the Department of Neurology, UNICAMP,
decades ago, and even before, under my medical residency and specialization in
Neurology at Sahlgrenska University Hospital (Gothenburg, Sweden). The prob-
lems and limitations of researches on these conditions are critically discussed from
the point of view of a systemic and interfunctional approach of cognition, as thor-
oughly presented in Parts I and III.
Preface ix

With this kind of approach, by showing the complexity of the human mind, I
hope this book will be useful to all those who are interested in doing research on
cognition disorders.

Campinas, São Paulo, Brazil Benito Damasceno


Acknowledgments

I am deeply grateful to all patients and colleagues of the Department of Neurology,


UNICAMP Medical School and Clinics Hospital (Brazil), for giving me the oppor-
tunity to work together and better understand the human mind and treat its disor-
ders. I am indebted particularly to those colleagues with whom I researched together,
namely, Fernando Cendes and Andrea Allesio in the area of epilepsy; Márcio
Balthazar, in dementia; Alfredo Damasceno and Leonilda Santos, in multiple scle-
rosis and neuroimmunology; and Edwiges Morato and Maria Irma Coudry, in neu-
rolinguistics (UNICAMP Aphasia Centre). Special thanks to Alfredo Damasceno
for reviewing and suggesting improvements to the manuscript. I am also thankful
for the invaluable support and grants given by CNPq (National Council for Scientific
and Technological Development, Brazil) and especially by FAPESP (São Paulo
Research Foundation, Brazil) all these years. And I cannot forget those colleagues
at Sahlgrenska University Hospital (Gothenburg, Sweden), who taught me neurol-
ogy (particularly Lorenz Bergmann), the fundamentals of neuropsychology (Peter
Borenstein), and neurophysiology (Gaby Bader) as part of my medical residency
and specialization in neurology.

xi
Contents

1 Introduction����������������������������������������������������������������������������������������������    1
1.1 Theoretical Approach������������������������������������������������������������������������    1
1.1.1 Introduction��������������������������������������������������������������������������    1
1.1.2 Cognition as a Dynamic Functional System������������������������    1
1.1.3 Historical-Cultural Origin of Cognition�������������������������������    3
1.2 Methodological Issues����������������������������������������������������������������������    4
1.2.1 Neuropsychological Diagnosis of the Impaired Basic
Mental Mechanisms and Lesion Localization����������������������    4
1.2.2 Brain-Behavior Correlations������������������������������������������������    6
1.3 Conclusion����������������������������������������������������������������������������������������   10
References��������������������������������������������������������������������������������������������������   11

Part I Cognitive Functions and Their Interrelationships


2 Sensation and Perception������������������������������������������������������������������������   15
2.1 Introduction��������������������������������������������������������������������������������������   15
2.2 Sensation ������������������������������������������������������������������������������������������   15
2.2.1 The Question of the Authenticity of Our Sensations
and Perceptions ��������������������������������������������������������������������   16
2.2.2 Sensations Basic Properties��������������������������������������������������   17
2.2.3 Sensory Information Contributes to Vital Bodily
Functions������������������������������������������������������������������������������   20
2.3 Perception ����������������������������������������������������������������������������������������   21
2.4 Conclusion����������������������������������������������������������������������������������������   23
References��������������������������������������������������������������������������������������������������   24
3 Attention ��������������������������������������������������������������������������������������������������   25
3.1 Introduction��������������������������������������������������������������������������������������   25
3.2 Types of Attention����������������������������������������������������������������������������   26
3.3 Attention Is Carried Out by a Complex Functional System ������������   28
3.4 Conclusion����������������������������������������������������������������������������������������   29
References��������������������������������������������������������������������������������������������������   30

xiii
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4 Memory����������������������������������������������������������������������������������������������������   33
4.1 Introduction��������������������������������������������������������������������������������������   33
4.2 Memory Processes����������������������������������������������������������������������������   33
4.3 Memory Systems������������������������������������������������������������������������������   36
4.4 Conclusion����������������������������������������������������������������������������������������   42
References��������������������������������������������������������������������������������������������������   43
5 Language��������������������������������������������������������������������������������������������������   47
5.1 Introduction��������������������������������������������������������������������������������������   47
5.2 Discourse and Pragmatics ����������������������������������������������������������������   48
5.3 Brain Lesion and the Classical Aphasia Syndromes������������������������   49
5.3.1 Boston Group Classification of Aphasias ����������������������������   51
5.3.2 Luria’s Classification������������������������������������������������������������   52
5.4 Brain Lesion and Disorders of Discourse ����������������������������������������   53
5.5 Conclusion����������������������������������������������������������������������������������������   55
References��������������������������������������������������������������������������������������������������   56
6 Cognition as a Mediated, Self-Organized, and Dynamic
Activity������������������������������������������������������������������������������������������������������   59
6.1 Introduction��������������������������������������������������������������������������������������   59
6.2 The Mediated Character of Cognition����������������������������������������������   59
6.3 Cognition as a Self-Organized Functional System ��������������������������   60
6.4 Cognition Conceived as a Kind of Activity��������������������������������������   61
6.5 The Dynamic Structure of the Mental Activity��������������������������������   64
6.6 Conclusion����������������������������������������������������������������������������������������   66
References��������������������������������������������������������������������������������������������������   67

Part II Historical-Cultural Origin of Cognition


7 Evolutionary Perspective������������������������������������������������������������������������   71
7.1 Introduction��������������������������������������������������������������������������������������   71
7.2 The Mind as the Product of a Biological and Social-­Cultural
Evolution������������������������������������������������������������������������������������������   71
7.3 Stages of the Phylogenetic Development of the Mind����������������������   73
7.4 Conclusion����������������������������������������������������������������������������������������   77
References��������������������������������������������������������������������������������������������������   78
8 Ontogenetic Perspective��������������������������������������������������������������������������   79
8.1 Introduction��������������������������������������������������������������������������������������   79
8.2 Early Cognitive-Cerebral Development��������������������������������������������   79
8.3 Social-Cultural Learning������������������������������������������������������������������   82
8.4 Social, Noncultural Learning������������������������������������������������������������   83
8.5 Conclusion����������������������������������������������������������������������������������������   83
References��������������������������������������������������������������������������������������������������   84
Contents xv

9 Role of Imitation and Appropriation in the Cognitive


Development ��������������������������������������������������������������������������������������������   87
9.1 Introduction��������������������������������������������������������������������������������������   87
9.2 Imitation Learning����������������������������������������������������������������������������   87
9.3 The Process of Appropriation of Adult’s Cognitive
Functioning by the Child������������������������������������������������������������������   90
9.4 Conclusion����������������������������������������������������������������������������������������   92
References��������������������������������������������������������������������������������������������������   93
10 Acquisition of Theory of Mind, Language, and Social
Cognition��������������������������������������������������������������������������������������������������   95
10.1 Introduction������������������������������������������������������������������������������������   95
10.2 Development of Theory of Mind, Empathy, and Social
Cognition����������������������������������������������������������������������������������������   96
10.3 Acquisition of Language����������������������������������������������������������������   97
10.3.1 Development of the Regulatory Function of Language
and of Logical and Discursive Reasoning��������������������������   99
10.4 Conclusion�������������������������������������������������������������������������������������� 101
References�������������������������������������������������������������������������������������������������� 102

Part III Neuropsychological Investigation: Methodological Issues


11 Systemic Approach and the Problem of Reciprocal Influences
of Mental Functions on Each Other ������������������������������������������������������ 107
11.1 Introduction������������������������������������������������������������������������������������ 107
11.2 Systemic Approach ������������������������������������������������������������������������ 108
11.3 Single and Double Dissociations���������������������������������������������������� 110
11.4 Conclusion�������������������������������������������������������������������������������������� 111
References�������������������������������������������������������������������������������������������������� 112
12 Brain-Behavior Correlations������������������������������������������������������������������ 113
12.1 Introduction������������������������������������������������������������������������������������ 113
12.2 The Challenge of Disclosing and “Localizing” the Basic
Defect Underlying a Syndrome������������������������������������������������������ 113
12.3 Choosing Appropriate Neuropathological Cases and Methods
for Valid Brain-Behavior Correlations�������������������������������������������� 117
12.4 Conclusion�������������������������������������������������������������������������������������� 119
References�������������������������������������������������������������������������������������������������� 120
13 Research Methods and Designs�������������������������������������������������������������� 123
13.1 Introduction������������������������������������������������������������������������������������ 123
13.2 Experimental Method���������������������������������������������������������������������� 123
13.3 Influential Confounding Variables�������������������������������������������������� 124
13.3.1 Subject Variables���������������������������������������������������������������� 124
13.3.2 Test Characteristics ������������������������������������������������������������ 127
13.3.3 Testing Situation ���������������������������������������������������������������� 128
xvi Contents

13.4 Study Design and Control of Subject Variables������������������������������ 129


13.5 Psychometric Tests�������������������������������������������������������������������������� 131
13.6 Case Studies (Single-Case, Multiple Cases) Versus
Group Studies���������������������������������������������������������������������������������� 132
13.7 Conclusion�������������������������������������������������������������������������������������� 134
References�������������������������������������������������������������������������������������������������� 135

Part IV Fundamentals of Statistics Applied to Biomedical


and Psychological Research
14 Elements of Statistics: Basic Concepts�������������������������������������������������� 141
14.1 Introduction������������������������������������������������������������������������������������ 141
14.2 Definition of Basic Concepts���������������������������������������������������������� 142
14.3 Levels of Measurement������������������������������������������������������������������ 143
14.4 Describing and Summarizing the Data ������������������������������������������ 144
14.5 Conclusion�������������������������������������������������������������������������������������� 146
References�������������������������������������������������������������������������������������������������� 147
15 Fundamentals of Statistical Analysis������������������������������������������������������ 149
15.1 Introduction������������������������������������������������������������������������������������ 149
15.2 Data Frequency Distribution���������������������������������������������������������� 149
15.3 Distribution of Sample Means and Their Properties���������������������� 153
15.4 Confidence Intervals ���������������������������������������������������������������������� 154
15.5 Conclusion�������������������������������������������������������������������������������������� 155
References�������������������������������������������������������������������������������������������������� 155
16 Hypothesis Testing ���������������������������������������������������������������������������������� 157
16.1 Introduction������������������������������������������������������������������������������������ 157
16.2 Hypothesis Testing�������������������������������������������������������������������������� 157
16.3 Statistical Significance and Its Limitations������������������������������������ 158
16.4 Effect Size and Statistical Power���������������������������������������������������� 159
16.5 One- or Two-Tailed Tests in Hypothesis Testing���������������������������� 161
16.6 Sample Size Calculation ���������������������������������������������������������������� 161
16.7 The Problem of Small Sample�������������������������������������������������������� 162
16.8 Conclusion�������������������������������������������������������������������������������������� 165
References�������������������������������������������������������������������������������������������������� 165
17 Choosing a Statistical Test���������������������������������������������������������������������� 167
17.1 Introduction������������������������������������������������������������������������������������ 167
17.2 Univariate Analysis ������������������������������������������������������������������������ 168
17.3 Bivariate Analysis �������������������������������������������������������������������������� 168
17.3.1 The Chi-Squared (χ2) Test�������������������������������������������������� 169
17.3.2 The t-Test���������������������������������������������������������������������������� 171
17.3.3 Correlation�������������������������������������������������������������������������� 173
17.3.4 Simple Linear Regression �������������������������������������������������� 175
Contents xvii

17.4 Correlation, Regression, Plausibility, and Causality���������������������� 179


17.5 Multivariable Analysis�������������������������������������������������������������������� 180
17.5.1 Analysis of Variance (ANOVA)������������������������������������������ 180
17.5.2 Multiple Regression������������������������������������������������������������ 182
17.6 Conclusion�������������������������������������������������������������������������������������� 183
References�������������������������������������������������������������������������������������������������� 184

Part V Methodological Issues in Research on Selected Conditions


18 Cognitive Research on Early Multiple Sclerosis ���������������������������������� 189
18.1 Introduction������������������������������������������������������������������������������������ 189
18.2 The Problem of Early MS Diagnosis���������������������������������������������� 190
18.3 Cognitive Impairment �������������������������������������������������������������������� 190
18.4 Cognitive Impairment and MS Neuropathology���������������������������� 191
18.5 Influence of Depression, Fatigue, Sleep Disturbance,
Comorbidities, and Side Effect of Drugs on Cognitive
Dysfunction������������������������������������������������������������������������������������ 192
18.6 Cognitive Assessment �������������������������������������������������������������������� 195
18.7 Conclusion�������������������������������������������������������������������������������������� 199
References�������������������������������������������������������������������������������������������������� 200
19 Temporal Lobe Epilepsy�������������������������������������������������������������������������� 207
19.1 Introduction������������������������������������������������������������������������������������ 207
19.2 Neurophysiological and Neuroimaging Investigation�������������������� 208
19.3 Neuropsychological Assessment���������������������������������������������������� 208
19.4 Conclusion�������������������������������������������������������������������������������������� 211
References�������������������������������������������������������������������������������������������������� 212
20 Mild Cognitive Impairment and Early Dementia�������������������������������� 215
20.1 Introduction������������������������������������������������������������������������������������ 215
20.2 Dementia ���������������������������������������������������������������������������������������� 216
20.3 Mild Cognitive Impairment and Prodromal Alzheimer’s
Disease�������������������������������������������������������������������������������������������� 217
20.4 Controversies Surrounding Biomarkers in the Early
Stages of Alzheimer’s Dementia���������������������������������������������������� 220
20.5 Preclinical AD and the Case Against an Exclusively
Biological Definition of the Disease ���������������������������������������������� 223
20.6 Preclinical and Prodromal AD: Neuropsychological Issues ���������� 227
20.7 Limitations of Conventional Criteria for MCI
and Prodromal AD�������������������������������������������������������������������������� 228
20.8 Conclusion�������������������������������������������������������������������������������������� 230
References�������������������������������������������������������������������������������������������������� 231

Index������������������������������������������������������������������������������������������������������������������ 237
Abbreviations

AD Alzheimer´s disease
ADNI Alzheimer´s Disease Neuroimaging Initiative
ADRDA Alzheimer´s Disease and Related Disorders Association
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANCOVA analysis of covariance
ANOVA analysis of variance
APOE apolipoprotein E
APP amyloid precursor protein
BDI Beck Depression Inventory
BDNF brain-derived neurotrophic factor
BICAMS Brief International Cognitive Assessment for Multiple Sclerosis
BNT Boston Naming Test
BRB-N Brief Repeatable Battery of Neuropsychological Tests
BVMT Brief Visuospatial Memory Test
CDR Clinical Dementia Rating
CSF cerebrospinal fluid
COWAT Controlled Oral Word Association Test
CVD cerebrovascular disease
CVLT California Verbal Learning Test
D-KEFS Delis-Kaplan Executive Function System
DMN default mode network
DSM Diagnostic and Statistical Manual of Mental Disorders
EDSS Expanded Disability Status Scale
EEG electroencephalography
FAQ Functional Assessment Questionnaire
FCSRT Free and Cued Selective Reminding Test
FDG fluorodeoxyglucose
FSMC Fatigue Scale for Motor and Cognitive Functions
FSS Fatigue Severity Scale
FTD frontotemporal degeneration
FTDP-17 Frontotemporal dementia and parkinsonism linked to chromosome 17

xix
xx Abbreviations

GM gray matter
IADL instrumental activities of daily life
ICD-10 International Statistical Classification of Diseases and Related Health
Problems – 10th Revision
ILAE International League Against Epilepsy
IWG International Working Group
LNI Luria´s Neuropsychological Investigation
MACFIMS Minimal Assessment of Cognitive Function in Multiple Sclerosis
MCI mild cognitive impairment
MADRS Montgomery-Åsberg Depression Rating Scale
MFIS Modified Fatigue Impact Scale
MMSE Mini-Mental State Examination
MRI magnetic resonance imaging
MS multiple sclerosis
MSFC MS Functional Composite
MTLE medial temporal lobe epilepsy
NFT neurofibrillary tangle
NIA-AA National Institute on Aging – Alzheimer’s Association
NINCDS National Institute of Neurological and Communicative Disorders and
Stroke
NMDA N-methyl-D-aspartate
PASAT Paced Auditory Serial Addition Test
PET positron emission tomography
PFC prefrontal cortex
PiB Pittsburgh compound B
PM prospective memory
PSEN presenilin
RAVLT Rey Auditory Verbal Learning Test
SDMT Symbol Digit Modalities Test
SPART 10/36 Spatial Recall Test
SPECT single photon emission computerized tomography
SRT-DR Selective Reminding Test – Delayed Recall
ToM theory of mind
WAIS-R Wechsler Adult Intelligence Scale – Revised
WLG Word List Generation
WM working memory
WMS Wechsler Memory Scale
Chapter 1
Introduction

1.1 Theoretical Approach

1.1.1 Introduction

Cognition is a set of processes by which knowledge is acquired, stored, and manipu-


lated in the mind. These processes start with sensation and comprise other interre-
lated mental actions involved in perception, attention, visual-spatial-motor abilities,
memory, language, and intellectual reasoning. As a component of the mind, cogni-
tion has reciprocal relationships with other noncognitive functions, such as emo-
tion, volition, and self. Cognitive functions are not isolated or a priori existing
“faculties” located in circumscribed brain center, but complex, distributed, and
dynamic functional systems, which represent the natural and social world by means
of signs (this is their mediated, semiotic nature) and results from the internalization
or appropriation by the individual of external actions and relations with things and
persons (their social-historical-cultural origin) [1, 2].

1.1.2 Cognition as a Dynamic Functional System

As a functional system, mind and cognition comprise a network of various basic


mental operations (processes) organized in a set of interconnected brain regions,
each region contributing with its specific operation to the functioning of the system
as a whole. This concept of functional system can be illustrated with the way we
solve a problem given orally, e.g., “John has 10 apples and Joe has 3 apples less than
John. How many apples do they have?” or “A man needed to cross a river using a
very small canoe. He had to bring three things across the river: a hen, a basket of
corn, and a fox. Because of the size of the canoe, he could only cross with one thing
at a time. If he crossed with the fox first, the hen would stay behind with the corn

© Springer Nature Switzerland AG 2020 1


B. Damasceno, Research on Cognition Disorders,
https://doi.org/10.1007/978-3-030-57267-9_1
2 1 Introduction

and eat it. If he took the basket of corn first, the fox would stay behind with the hen
and eat it. What would he have to do to get all three things across the river?”. The
solution requires an ensemble of various crucial mental operations and their corre-
sponding brain regions or networks, such as (1) phonemic analysis and synthesis for
understanding words (left superior-posterior temporal gyrus and neighboring asso-
ciative cortex); (2) semantic analysis of sentences and the text as a whole as well as
interpretation of the logico-grammatical relationship expressed by the phrase “less
than,” plus symbolic-spatial reasoning involved in the subtraction 10 minus 3
(mainly left inferior parietal and neighboring lateral temporal associative cortex);
(3) memory processes for maintaining online in the focus of consciousness, both
short-term, new incoming information (sensory-perceptive, spatial, verbal-­
phonological) and long-term, old information, collected from episodic, semantic,
and procedural memory (prefrontal in connection with temporal regions); and (4)
hypothesis testing, establishment of a goal and plan of solution, monitoring the
execution of the plan, and lastly verifying whether the result obtained is according
to the final question and to the data and constraints of the problem (prefrontal
regions).
Another characteristic of the mind’s functional system is its dynamic structure,
that is, the composition of the whole set of mental operations and brain regions’
changes from moment to moment insofar as each task consecutively switches from
one to the other. At each moment, each intermediary task requires a different ensem-
ble of cognitive operations suitable to achieve the main objective (i.e., to achieve the
goal or to answer to the final question of a problem). Besides these cognitive opera-
tions, an adequate level of motivation, volition, and affective state is critical. So, the
final objective of the activity as a whole remains constant, but the methods and
cognitive operations involved can vary [3].
This conception of the mind represents a great theoretical-methodological con-
tribution to basic and clinical scientific research on mental-cognitive issues, since it
takes into account relationships and reciprocal influences between task-relevant
psychological variables, whose unique (independent) contribution to the fulfillment
of the task can be controlled beforehand (when planning the study) or can be deter-
mined by multivariable statistical analysis after data collection. Based on this con-
ception, a clinical neuropsychological research has also to take into consideration
the influences exerted by symptoms or syndromes on each other, for example, the
interplay between depression, apathy, fatigue, sleep disturbance, psychosocial
stress, and side effect of drugs. In clinical practice, a thorough anamnesis with
detailed analysis of each of these accompanying disorders or comorbidities may
disclose which of them is the main or primary contributor to the cognitive
impairment.
As regards the mediated character of cognition, it is given by the fact that the
individual relates himself with other things and persons not directly, but by means
of the signals and signs (mediators) which represent these things, persons, their
properties, and behaviors. Sensations are the first step to getting knowledge about
the outside world. The physical, chemical, and spatial-temporal properties of exter-
nal things and phenomena stimulate the sensory cells’ receptors, where these prop-
1.1 Theoretical Approach 3

erties are transduced and converted into trains of action potentials along the sensory
cells’ axons, whose frequency and rhythm codify (as neural codes) the information
about those external things. From the most primitive and simple signals (as those of
conditioned reflexes) to the signs of human language (e.g., words), the meaning of
the mediators becomes more generalized and abstract [4].

1.1.3 Historical-Cultural Origin of Cognition

The historical-social-cultural origin of cognition is based on the appropriation


(internalization) by the individual of external, practical relationships, and interac-
tions with other people and objects. These interactions, particularly those of coop-
erative labor activities, are mediated by two kinds of instruments: material (tools,
artifacts) and psychological (signs, words), the first ones for acting on nature and
the second ones, on other people [5]. The appropriation process, firstly by imitation
learning and then through the subsequent mastery of these instruments, particularly
the signs of language (words), enables the individual to construct his/her internal
language, ideal actions, and thought as action, which will precede any external
activity [6, 7]. For this reason, cognition may be conceived as a kind of internal
(mental and cerebral) version of the external, vitally, and socially relevant activity,
as we have seen in problem-solving. The joint social practice with other people is a
sine qua non condition for the acquisition of a normal healthy human mind. The
lack or deprivation of adequate sensory, linguistic, and socioemotional interaction
in critical periods of the mental-cerebral development can lead to serious cognitive
and behavioral consequences, as found in orphaned and abandoned children raised
in institutions [8, 9]. According to observational and interventional case-control
studies in these children, intellectual-executive and memory functions are the most
impaired, accompanied by psychiatric disturbances ranging from autistic-like to
inattentive, hyperactive, and aggressive behavior [10–12]. In children with early
psychosocial deprivation, neuroimaging studies have shown structural abnormali-
ties predominantly in prefrontal and medial temporal regions, with reduced con-
nectivity in frontal, temporal, and parietal white matter, including components of
both uncinate (amygdala-frontal connection) and superior longitudinal fasciculi
(parietal-temporal-occipital connection to frontal regions), which are respectively
involved in emotional control and higher psychological functions. These white mat-
ter abnormalities have been correlated to duration of time in the orphanage and to
scores of inattention and hyperactivity [13].
4 1 Introduction

1.2 Methodological Issues

Research on cognitive disorders may have as objectives (1) to detect which basic
mechanism or mental operation is impaired as well as which symptom or syndrome
is primary or secondary and, in this way, to diagnose the regional distribution of the
brain lesion or dysfunction, yielding valuable information for establishing an appro-
priate rehabilitation program; (2) to provide a baseline and profile of neuropsycho-
logical impairment for future comparisons; and (3) to predict the patient’s behavior
in real-world settings on the basis of his/her performance on neuropsychological
tests. The first and third objectives are particularly challenging due to the complex,
interrelated, and dynamic nature of our mental functions.

1.2.1  europsychological Diagnosis of the Impaired Basic


N
Mental Mechanisms and Lesion Localization

Modern techniques as magnetic resonance imaging (MRI) can localize the brain
damage with high accuracy, but an MRI may not show signs of lesion where the
neuropsychological evaluation indicates there is a dysfunction, as in patients exam-
ined 2 h after an acute ischemic stroke manifested exclusively as Wernicke-like
aphasia or in the early phase of Alzheimer’s disease presenting solely with episodic
memory impairment (amnesia). Neuropsychological evaluation takes into account
the following principles proposed by Luria [2] and Mesulam [14]:
1. Some brain regions, especially those of so-called convergence-divergence zones
or hubs (e.g., left temporal-parietal junction), process some basic mental opera-
tions (e.g., spatial reasoning) needed for performing different complex tasks
(e.g., construction of a model using multicolored Kohs cubes, chess game, left-­
right orientation, subtraction 51–17, and understanding of relational expressions
as “the father’s brother”). Therefore, a lesion in such a region (e.g., left inferior
parietal) will produce not an isolated symptom but a whole syndrome compris-
ing, e.g., constructional apraxia, acalculia, spatial disorientation, and aphasic
difficulties – also known as Gerstmann syndrome. As a corollary, the finding of
such a syndrome obtained by means of a comprehensive neuropsychological
assessment strongly suggests a lesion in that brain region.
2. The various basic operations required to fulfill a complex task can be impaired
by damage to a brain region (or interconnecting pathways) that processes any of
them. For instance, incapacity to solve a problem may be due to lesion in any
brain region that process some of the basic operations needed for resolving it.
So, it may result from a working memory and/or intellectual-executive dysfunc-
tion (prefrontal lesion), aphasia (left temporal cortex), or acalculia (left inferior
parietal region).
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1.2 Methodological Issues 5

Therefore, to disclose the impaired basic mental operation and, by inference, the
corresponding brain region that is damaged, we need a comprehensive battery of
appropriate tests, including control tests (counterproofs) and control conditions.
One crucial control condition is the comparison of the patient’s test performance
with that of healthy subjects matched to the patient as regards variables that can
influence performance, such as age, sex, and educational level. This comparison is
necessary for ascribing the patient’s inferior performance to his brain lesion.
The selection of the tests is based on their accuracy to detect and measure those
basic mental operations hypothetically required for executing the complex task in
which the subject is disabled. This can be illustrated with the neuropsychological
investigation of patients with medial temporal lobe epilepsy (MTLE), the most
common epilepsy type in adults, frequently associated with medial temporal lesions
and memory decline, but presenting good outcome after resection of the epilepto-
genic focus. The best surgical outcomes are obtained when the results of neuropsy-
chological, electroencephalographic (video-EEG-telemetry), and neuroimaging
(e.g., MRI, SPECT, PET) are concordant, each one independently indicating the
same side and local of the brain dysfunction. In MTLE cases, the main challenge to
the neuropsychologist is to localize the brain dysfunction without knowing or being
influenced by the EEG and neuroimaging data. For attaining this goal, the neuropsy-
chological investigation has to satisfy the following conditions:
1. As regards memory, the test battery has to take into account the existence of its
different subtypes (episodic, semantic, working memory) as well as the putative
functional differences between the left and right temporal lobes concerning rep-
resentation of verbal and visual-spatial memory. According to the so-called
material specific memory model (MSMM) [15, 16], the left temporal lobe is
dominant for mediating memory for verbal material (e.g., list of abstract words)
and the right one, for nonverbal material (e.g., abstract designs). This material-­
specific lateralization has been confirmed strongly as regards the relation
between left temporal epileptogenic focus (or lesion) and verbal memory [17–
21] but weakly as concerns right-sided focus (lesion) and nonverbal (visual, spa-
tial) memory deficits, probably due to the verbalizability of the visual material
employed or because visual-spatial memory has a more diffuse or bilateral brain
representation. Moreover, there is “paradoxical” evidence of impairment of non-
verbal (visual, spatial) memory in cases with left hippocampal sclerosis or left
anterior temporal resection [22], as well as of verbal memory after right tempo-
ral resection [23].
2. Another problem is that the patient’s inferior performance on a memory (learn-
ing) task may be caused not by a primary disorder of episodic memory (or medial
temporal lesion) but by impairment of another cognitive function that is crucial
for executing that task (e.g., auditory or visual perception, attention, verbal flu-
ency), or it may also be due to a more widespread or diffuse disturbance (e.g.,
depression, fatigue, drowsiness, side effect of drugs) whose influence should
have been controlled, minimized, or removed. For this reason, all these variables
(i.e., other non-memory cognitive functions or diffuse disturbances) that can
6 1 Introduction

influence the execution of a memory task have to be assessed by means of appro-


priate control tests (counterproofs), for example, examining visual perception
with Poppelreuter’s overlapping figures [2] or form discrimination [24]; atten-
tion with “A” Random Letter Test [25] or WAIS-R digit span [26]; verbal fluency
with category (animals) or FAS [27]; mood with the seven items of Beck’s
Depression Inventory Fast Screen (BDI-FS) [28]; and fatigue with the Modified
Fatigue Impact Scale (MFIS) [29, 30]; or the Fatigue Scale for Motor and
Cognitive Functions (FSMC) [31]. An issue here is that depression and fatigue
are subjective overlapping syndromes, with fatigue being a component of the
DSM-5 diagnostic criteria for depression [32], but the differentiation between
both may be achieved by employing the BDI-FS plus MFIS or FSMC. BDI-FS
prioritizes depressive thought content (e.g., feelings of worthlessness or inap-
propriate guilt) and mood (e.g., dysphoria, anhedonia) and excludes items in
which depression is confounded with fatigue or cognitive impairment; and the
MFIS or FSMC measures specifically fatigue (both physical and cognitive, psy-
chosocial fatigue).

1.2.2 Brain-Behavior Correlations

1.2.2.1 Control of Influential Variables: Study Design

The relationship between a patient’s brain disease or lesion A (e.g., hippocampal


atrophy) and his/her cognitive-behavioral syndrome B (e.g., amnesia) or perfor-
mance on neuropsychological tests is not straightforward or linear, but mediated by
extraneous influential variables other than the lesion itself, e.g., age, education,
mood state, psychosocial stress, cognitive and brain reserve, and comorbidities
(Fig. 1.1).
Variable is any characteristic of persons, things, or phenomena, which can vary,
presenting different types, levels, or values. A variable is called independent (IV;
e.g., age) when it can affect another one, called dependent variable (DV; e.g., logical

Fig. 1.1 Multiple factors


(C, D, E, F, G, H) that can
influence (modify) the
relationship between a
brain lesion (A) and a
cognitive syndrome (B).
1.2 Methodological Issues 7

reasoning). In research on cognition, the investigator manipulates an IV and looks


for changes in a DV. The power of such a research is given by its ability to ensure
that only the IV is permitted to vary across the conditions of the testing. So, the
investigator has to control (remove) the influence of any variable (other than the IV
being studied) which could have an effect on the DV; otherwise, the results of the
investigation may be difficult to be interpreted and inconclusive. These extraneous
variables are called covariates. A covariate is called confounder (e.g., age, in the
example of Fig. 1.1) when it influences both the IV that is being studied (e.g., hip-
pocampal atrophy) and the DV or outcome (amnestic syndrome or memory perfor-
mance), since it is known that aging leads to both increasing hippocampal atrophy
and memory impairment. Another kind of covariate is the mediator, which occurs,
for example, when an IV (e.g., temporal-limbic encephalitis) can lead to change in
a covariate, e.g., mood state (manifested as an asthenoemotional syndrome), which
in its turn leads to change in a DV, e.g., performance on memory tests. In this case,
the covariate “mood state” is a mediator.
Test performance may be influenced by variables related to the subject, to the test
(e.g., type of stimulus, psychometric and metacognitive characteristics, previous
instructions), or to the testing situation (e.g., local with bothersome light, tempera-
ture, or noise; the experimenter’s strange or exaggerated appearance, attitude, and
behavior). Among subject variables, age and education are the most important, but
cognitive performance may also be influenced by sex, handedness, intelligence
level, motivation, humor state, variations of the individual’s circadian rhythm, side
effect of drugs, polyglotism, and previous experience with the proposed tasks.
In research in the fields of neuropsychology, behavioral neurology, and cognitive
neuroscience, control of variables is achieved by means of an experiment, which is
a procedure carried out under controlled conditions, consisting in intervening,
manipulating, and altering the state of the participants. An experiment is, for this
reason, the best method for testing hypothesis and verifying cause-and-effect rela-
tionships or, at least, associations between events. An experimental design may be
“cross-sectional,” by collecting data from different subjects that belong to two or
more groups at a single point in time, or “longitudinal,” or “prospective,” by gather-
ing data from the same sample of subjects on two or more occasions. The longitudi-
nal design has higher probability to provide evidence supporting cause-and-effect
relationships.
The influence of subject variables can be removed or minimized by means of
group studies, which can adopt (1) a “within-subject” (also called “repeated mea-
sures”) design, using the same subjects in each of the experimental conditions and
testing sessions, or (2) a “between-subjects” or “between-groups” design, allocating
different subjects in each experimental group by means of randomization and
matching.
In randomization, each subject gets a number or code which has equal probabil-
ity as all other subject numbers and codes for being randomly chosen and allocated
in each subgroup. Randomization does not eliminate interindividual differences
(subject variables) but reduces their effect on the performance of each subgroup.
Another way to reduce the influence of subject variables is by increasing sample
8 1 Introduction

size. Nevertheless, randomization alone cannot increase the sensitivity of an


­experiment in detecting a small effect of an IV on a DV, but this deficiency is over-
come by matching, that is, by selecting pairs of subjects with similar characteristics
(age, sex, education, intelligence) which can influence test performance and have an
effect on the DV and then allocating randomly each subject of the pair in each sub-
group. In summary, influential variables should be controlled or maintained the
same between testing sessions of the same individual or between groups of indi-
viduals being compared. In case-control group studies, confounders should be
assigned equally to both groups.
Nowadays, grant-giving institutions require that the project present, already in its
planning phase, before data collection, a detailed description of study design, meth-
ods for controlling influential variables (especially confounders), and type of statis-
tical analysis of the data. For this purpose, the investigator has to know beforehand
which covariates would be the most influential in the relationship between the IV
and the DV (outcome) to be studied. If these requirements were not fulfilled before-
hand, then, after the data have been collected, a multivariate statistical analysis may
disclose that, after adjusting for the most relevant covariates, a brain lesion or dys-
function (e.g., hippocampal atrophy or epileptogenic focus) has an independent per-
centage of contribution to the low memory scores of the patients. In such a situation,
by using a multivariate analysis (such as backward stepwise regression or ANCOVA),
we can demonstrate a primary, memory-specific impairment associated with that
brain dysfunction.
As compared to case studies, group studies are more complex, require large
enough sample sizes, take longer time due to rigorous inclusion criteria, but are the
best method for balancing interindividual variations in biological, sociocultural, and
psychological characteristics, as well as for increasing intragroup homogeneity and
for gathering more reliable data in clinical trials and brain-behavior correlation
studies.
The within-subject design has the advantages of maximally removing the influ-
ence of interindividual variability and of requiring fewer participants, since the sub-
jects performing in later repeated testings are controls for themselves performing in
former ones (e.g., in the baseline evaluation). In spite of the advantages of the
within-subject design, two problems may arise with it: (1) the order effect, with the
subject’s performance on the second testing being influenced by his/her perfor-
mance on the first one due to practice or fatigue (this effect may be overcome by
randomizing the order of the tests among all subjects of the group, with half the
subjects following the order A → B and the other half the inverse order B → A), and
(2) the carryover effect, with the subjects remembering some items (e.g., words) of
the first testing and intrusively introducing them in the second or third testing, even
when tested with different items (e.g., another list of words).
The between-groups design is often used in case-control clinical trials compris-
ing a subgroup of cases that receive the new intervention or treatment being tested
(e.g., a new drug, surgical procedure, or rehabilitation method) and the controls,
which do not get the new treatment but instead are given a placebo, a traditional
treatment, or no treatment at all. A condition for gathering reliable data and detect-
1.2 Methodological Issues 9

ing even small treatment effects in clinical trials, besides a large enough sample
size, is double-blinding, that is, neither the participant subjects nor the investigators
know the kind of treatment the participants are receiving.

1.2.2.2 Issues Related to Lesion Analysis

As regards the lesion, a cognitive-behavioral syndrome cannot be explained exclu-


sively by the loss of function supposedly performed by the damaged brain region
[33], since the syndrome results from the combination of other factors, which may
be (1) psychological (motivation, humor state), (2) neuropsychological (systemic
and dynamic character of mental functions, type and severity of the cognitive disor-
der), and (3) dysfunction of other intact brain structures interconnected to the dam-
aged one, since lesion in one region causes change of neurotransmission,
excitation-inhibition balance, and blood flow in other neighboring and distant brain
regions. Some of these regions that normally were activated or inhibited by the dam-
aged one become denervated and consequently hypo- or hyperactive, in this way
also producing symptoms and contributing to the syndrome as a whole. In addition,
there is a continuous postlesional transformation of the syndrome (Leischner’s
“syndromenwandel”) [34] due to an interplay between secondary axonal degenera-
tion, functional reorganization, and recovery (plasticity). A typical example is the
case of an acute ischemic stroke causing initially a global aphasia, which evolves
after months to a Broca’s aphasia. For all these reasons, to localize a lesion even
with high-resolution MRI does not imply in localizing in the same region the whole
syndrome.
On the other hand, the image of a lesion seen on MRI may not correspond to the
real degree of nervous tissue (cells and axons) destroyed, as happens in cases of
space-occupying lesions (e.g., parenchymal hematoma or infiltrating neoplastic
tumor), in which the abnormal imaging area does contain functionally competent
neurons and fibers. For this reason, for valid brain-behavior correlations in studies
of groups of patients, Damasio and Damasio [35, 36] suggested to include preferen-
tially ischemic stroke (infarction) in its chronic phase, more than 3 months old,
when the abnormal MRI image will correspond to actual (complete or partial) brain
parenchyma destroyed and the resultant syndrome will be in stable phase, thus
allowing safer brain-behavior correlations. As regards such correlations, structural
MRI also has other limitations: (1) its modularity assumption that cognitive func-
tions are mapped in functional modules which would have the same location in
different individuals, not taking into account individual variations in neural-­
cognitive organization nor considering that natural lesions (diseases) may be spread
beyond the limits of such functional modules [37], and (2) its low temporal resolu-
tion as regards detection of functional changes that occur in other brain regions
following the acute phase of a focal lesion. The combination of structural and perfu-
sion imaging [38] as well as of functional MRI (fMRI) has partly overcome this last
limitation. In fMRI, stimuli or tasks are presented to the subject, leading to increase
in blood flow and ratio of oxygenated to deoxygenated hemoglobin, which creates
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Web bent down to look at the man. He wasn't dead, but he was out
cold. Scared damn near to death. Web was amused, grinned once
very swiftly. If this was a sample, these aliens weren't much.
He picked up the old man, light and wispy as a bundle of leaves, and
carried him under one arm into the big living room which opened off
of the hall. He thought better of turning on a light, slumped the old
man on a couch and sat down beside him.
A street bulb outside the house threw a white soft glow of light into
the room. That was enough to see by for his purposes. He moved
over on the couch to a position from which he could see the door.
And then, in darkness, he waited.
It was several minutes before the old man moved. Web had time to
think, to form a plan. The first thing that moved in Web's mind was
a wonder of why in heck the old man should have fainted, and then
it occurred to him that this thing here was alien, truly alien, and
probably had a science so far beyond ours as to be impossible to
comprehend. He would undoubtedly be long-lived. Web thought;
could just as well be immortal.
But anyway, no matter what else he was, it was pretty sure that he
lived a long while, and death, any death, was a rare thing among his
people. Hence the unusual, to an Earthman, fear of dying. It figured.
Humans fear dying all right. But a lot of them face it every day as
part of their jobs, because life on Earth must be something like a
jungle compared to the germ-free, war-free, super-sanitary world of
the future. Death to a man like this would be quite a fearful thing.
And so the collapse.
And a weapon for Web.
He smiled in the darkness, cruelly, as the alien stirred. He would find
out from this man whatever he wanted to know.
Awake at last, with Web above him like a huge black mountain, the
old man nearly fainted again. But he managed to recover slowly, in a
state of really pitiful terror. He had known from the beginning that
Web was not a Galactic—a Galactic would never have approached in
person. The thought helped him to survive. But even then this
Earthman was a barbarian, an unaccountable man with no scruples
against killing, and Web was perfectly right about the fear of death.
The alien talked.
For a while he babbled, but then it began to make sense.
He told about the coming extinction of his race, and the plan for
interbreeding which would save it. He had been on Earth, he said,
for several years, choosing specimens for test purposes. The tests
had proved positive and the first step of selection was almost
completed. He had been stationed as a real doctor with a real
practice, so that he would have the opportunity of giving preliminary
physical examinations and passing on the names of potentially
acceptable candidates. And there were many doctors like him spread
all over the world. Since the United States was by far the Earth's
healthiest country of any size, most of the selecting had been done
right here.
"But what did you do with the men in the satellite?" Web asked,
doing his best to follow but fast losing ground.
"How did you know—?" And then the alien almost collapsed again.
He had heard, undoubtedly, of the one man that had escaped from
the satellite. But that had been a Galactic—
"Why did you do that, kill all those men, and how?"
Web shook him, the alien yelped feebly, then babbled it out.
"The satellite was in a very dangerous position. It could see all our
intercontinental travel, the ships we have going and coming daily. It
would undoubtedly warn the planet of what it saw. But we could not
simply destroy it. Blame for that might conceivably be placed on
your enemies, and you are such unstable peop—that is—we—there
was no need for a general war. We could not risk that, being
ourselves just as vulnerable to atomic attack as any life. So we—
removed the men on the satellite."
"How, dammit, how?"
When he swore the alien jumped.
"Through devices which you—if you do not already know, you
cannot be—oh—yes—I will tell, I will tell—" The old man searched
desperately for an explanation. "Your body has—every body is held
together by electric forces. By million upon millions of tiny electric
currents. The atoms of any body are kept in position by a—by an
attraction between them. Now, if that attraction is nullified, the
atoms will drift apart, disperse. The atoms will no longer exist in any
form. That was what happened to the men in the satellite. They
were—turned off."
Web sat perfectly still for a long moment. Then he said swiftly,
viciously:
"But why didn't it get me?"
The alien writhed on the couch.
"Your blood must be different. We thought you were a Galactic. Your
body chemistry is unusual, your—your charge is different."
Once again Web sat in silence, trying to follow that. Galactic and
different blood. But he wrenched his mind away. The sun would be
up soon and he would have to be out of here quickly. He would need
to know where their main base was. Then it was the army's turn.
Although what could the army do?
He got the location out of the old man. It was surprisingly near to
Chicago.
And the time of the first take-off, the first shipment, would be that
night.
He rose to leave. Then he turned back to the old man.
He debated it for a moment, but saw nothing else possible. The old
man knew who he was and where he was going, and what he knew.
He could not leave the old man to warn the others. The old man
knew that too, looked up at him and saved him the trouble.
He died just before Web's great hands reached him.

VII

Within the next hour he had a gun, taken from an amiable but
unfortunate young cop who had the courtesy to stop and give him a
match on a dark back street. He was sincerely sorry for that,
knowing what would happen to the cop, but he was also acutely
aware that he needed the gun a hell of a lot more than the cop did,
even if this was Chicago.
Later on, when the sun was up, he reconsidered. It occurred to him
that where he was going noise would be no virtue, not if he was
going in alone. So he bought himself a knife—Bowie, with a double
edged tip. Anyway, he had been schooled in knives in jump school,
and he knew how to use one even better than a wild .45. The thing
to do now was get within reach.
A cab took him to the bus terminal. It was a beautiful morning, brisk
and clear and cold, and on the way he picked up three Faktors.
At discreet intervals, they followed him into the terminal. He did not
notice them. They ringed him at a distance, following a set plan of
destruction, prepared to close in. Since there had been no time for
another recording, Kunklin and Prule had no choice. The three
Faktors died at once, in their tracks, in separate parts of the waiting
room.
It was a short while before the slumping men were noticed and the
uproar began. By that time Web was outside boarding a bus, and he
went on his way knowing nothing at all of the Faktors, nor of the
unfortunate incident that immediately befell the Galactics.
He rode the bus for two hours. As he got nearer and nearer to his
destination his resolve began to slip away. He was utterly alone, and
these enemies were alien. What in heck could he accomplish?
The bus pulled into a town called Alford just before noon. He
stepped down into the quiet street. There were no aliens around,
none that he could tell. He decided that there was probably no sense
in waiting for the dark. He did not know his way and the layout
would be important, so he decided to go up into the hills right away.
It was a long walk. He stayed with the road for about two miles,
then cut off abruptly into the woods. The ground became steeper, he
began to climb.
He had not gone forty feet before he tripped the first alarm.

The catastrophe, which neither Kunklin nor Prule had anticipated,


occurred as the result of a power failure.
Continued operation of the machine known as the "bender," together
with the enormous power drain of the anti-gravity webs they used to
float back and forth, had sapped the power of their suits down
below danger level. The one last burst which destroyed the three
Faktors reduced that power completely.
Both Kunklin and Prule became immediately visible.
They caused quite a stir.
Dressed as they were in white, satin-like suits, with glass bowl
helmets on their heads and a large back pack sprouting antennae in
all directions, they were an instantaneous focus of interest in the bus
terminal.
They were greatly annoyed, and also somewhat embarrassed.
"Galactic obscenity," said Kunklin, as a crowd gathered, "I thought
you recharged the suits."
"I thought you did," muttered Prule anxiously. "But let's get out of
here. Which way is the ship?"
They began to walk forward toward the door and the curious,
grinning crowd parted.
"It's way down this wide street. Oh fine!" Kunklin swore gloomily,
attempting at the same time to keep his face impassive. Fortunately,
Earthmen were humanoid. If they were not, of course, the Galactics
would never have allowed this to happen. And if experience on other
planets of this culture level was any judge, these people here would
think the Galactics and the suits were some kind of stunt. But
though this accident had happened quite often to other Galactic
agents, it had never happened to them, and they were
apprehensive. They eyed the crowd warily as they walked.
Grinning, giggling, pointing, the crowd eyed them back, and
followed.
Out into the street they went, two tall, undeniably weird-looking
men unable to keep their embarrassment from their faces. One
wide-eyed little boy ran up to Prule, grabbed at his sleeve with taffy-
smeared fingers. He chirped loudly to his parents to "looka the space
men." The mother came up, politely disengaged his fingers, gave a
smiling, unintelligible apology to Prule. Prule nodded as graciously as
he could, tried to walk faster.
"Listen," Prule groaned, "the power is too low to work the translator.
Suppose we're stopped? We can't talk to them."
"Here comes one in a uniform," said Kunklin, beginning to perspire.
"Police?"
"Yes."
"I suggest we run."
They broke into a trot. The crowd around them had grown rapidly
and began to trot with them, wondering where the show would take
place. The policeman ran too.
They let out their speed. Now a whole host of people began to shout
and new ones joined them, running, as they crossed a main street
against a light.
"Faster," grunted Kunklin.
Prule swore. "I can't. The suit's too heavy."
"Just a little way. When we get to the ship we'll put on a
demonstration."
They tore down the avenue, narrowly evading children, old ladies,
and newsstands. Two more blue-coated officials joined in the chase,
converging and blowing whistles. Several more were coming up in
front of them when they finally reached the ship.
They stopped in the center of the wide street. Traffic screeched to a
halt on all sides.
"Are you sure it's here?"
Kunklin looked around uneasily, then spied the faint hazy circle of
the opening, several feet in the air above them. He pushed at his
anti-gravity knob, felt himself lightening, but not lifting. He swore.
The crowd was reaching them, small boys and men lurched to a stop
around them.
"They're waiting for us to do something," Prule hissed.
"Quick! Before the police get here! Jump!"
Prule looked up helplessly at the hazy circle.
"How"—he began, but Kunklin pushed him aside, assumed a broad
stance in the center of the crowd. He thrust his arms outward
dramatically, as if for silence. Just then the first cop broke through
and into the center of the circle and began to speak virtuously,
angrily, in the manner of cops, but the people around him were
staring at Kunklin and waiting expectantly.
"Well," said Kunklin, speaking cheerfully in Galactic, "it's been fun."
He threw the anti-gravity to full power, waited till he could feel that
the lift would no longer increase. It was not enough to get him off
the ground, but he now weighed next to nothing. He crouched, then
leaped for the haze above. He shot up like a rocket, went through
the circle and disappeared.
A moment later Prule followed him. As he sailed up through the haze
the ship became immediately visible above, he reached out and
caught on to a rung of the ladder below Kunklin. Thankfully, wearily,
not bothering to look down at the stunned, open-mouthed crowd
which he could see below him but which could no longer see him, he
followed Kunklin up into the ship.
Kunklin did not wait at the airlock, he ran quickly away. Prule,
puffing, paused to look down at last on the crowd below. Their
ascent had been a success. The crowd was beginning to applaud.
Prule closed the airlock and the invisible, untouchable ship lifted. He
went to join Kunklin. The big Galactic was bent over the controls,
guiding the ship not upward—as Prule had thought—but horizontally
down the length of the wide street.
"Eh?" said Prule.
"Got to get a live Faktor," Kunklin said anxiously, his eyes glued to
the viewscreen. "We've lost the Earthman. He could be anywhere
now, and we can't help him. He may be headed for the Faktor's main
base. If so he will be killed. We've got to get to the base first."
Prule pursed his lips. "If he dies on our account, just because of
your foolish idea to use him—"
"I know," Kunklin cut in. "So we need a Faktor to tell us where the
base is. They're probably all over this city. I think I even saw one in
the crowd." He stopped. "That's another thing," he said unhappily,
"if there were Faktors in the crowd, they'll know a Galactic ship is
here."
Prule grunted, peered down at the left side of the screen.
"Look, isn't that one?"
He indicated a small, furtive-looking man who was walking swiftly
away from the area they had just left.
Kunklin adjusted for a close view.
"Yep." He moved to the instrument panel, worked carefully at a
traversing mechanism. "Get down to the airlock. We'll suck him up."
"He'll die of fright," Prule predicted. "They always do."
Kunklin shrugged. "We have to try. Maybe this will be a strong one."
"Let's hope so."
Prule readied himself at the open airlock. Kunklin threw a switch,
there was a deep, subtle hum, and a magnetic beam dosed down on
the man below. He flipped straight up toward the ship, like a hooked
minnow.
But he was not one of the stronger Faktors. He was dead before he
reached the door.

In the late afternoon, when the wind had died and the day was
quiet, the door opened.
The same two men—she had begun to be able to tell them apart—
came in and, this time, bowed.
Ivy yawned, rose up on an elbow and blinked her eyes.
The two men, surprised, stared at her.
"All right, what is it?" Ivy said as briskly as she could, trying to force
down the sudden fear. "Stop that damned bowing. A sillier bunch of
skinny idiots I never saw. Men! Huh! You're dying out, all right,
that's obvious."
The two men looked at each other. Then one of them recaptured his
grin.
"It is time for your breeding," he said lecherously.
Ivy yawned again, started to rise.
"Okay, I'll be with you in a minute. I hope it doesn't take too long.
I've lost a lot of sleep."
She managed to stand up calmly, with composure. The only thing
she could think of to do now was to regard this whole thing lightly,
and to make an occasional remark about the rather obvious defects
of her captors.
There was no sense in collapsing.
The two men, puzzled, followed her with their eyes as she fluffed up
her hair.
"No need of that," one of them said quickly, "you will be prepared by
others."
Ivy let her hair fall. "Okay Oscar. Whatever you say." In a very
unladylike manner, she yawned again, scratched herself. She grinned
at them both.
"I don't mean to be nasty, fellas, but why don't you pull up a chair
for a minute? Old guys like you shouldn't be running around all day
—"
The near one growled. The other one restrained him, smiled thinly.
"We have no need of rest," he said slowly. "We possess a certain—
vitality." His smile broadened. "As you shall presently see for
yourself."
Ivy did not look at him, walked suddenly past him and out the door.
They made a motion to grab her, but held back as she stopped. She
stood in the afternoon sun and stretched lazily.
"To your left," the man behind her said.
She waited for a moment, and then she walked. She strode upon
bare ground, upon soft grass, unable to be flippant now, looking
stiffly ahead toward a flat gray building. The door was open and she
could see the far wall, which was richly hung and colored in a
strange deep red. The two men left her at the door, where another
man, very old and white gowned and prissy, took her by the arm.
The man prepared her. She dropped all pretense at hardness, at
disinterest, and sat like a stone. In with the other, the breeder, she
would have to be icy. She became vaguely aware of a thick
fragrance around her, a musky, oily smell. Then the man released
her. She was prepared. He stood her up, waved at the door at the
far end of the room.
"There," he said without interest, turning away.
She took a deep breath and walked forward.

It was a long way up and Web went most of the way at a crouch,
the knife and the gun both ready at his belt. He had taken off his
coat and tie; it was chilly in the woods but he did not feel it.
Four miles north of Alford, the old man had said. Just a half mile off
the highway, on the tallest hill, the really steep one. He kept the
highway to his right going up, beginning to wonder at last if the
alien had told the truth. For all he knew, the camp might really be in
northern Tibet, and he could be stealing his way ever so stealthily
through total emptiness. But no. The old man had been scared to
death. Literally. And anyway, the thing he was walking into was
undoubtedly a trap, and knowing it did not do much good.
He cleared the first rise and climbed in among some rocks. Nearby
below he could see the highway, empty. The sun was high in the
afternoon. Four miles was not a long way, even crouching, and he
could probably make it before dark. In the dark shadows of the
bushes around him, nothing moved. He went up the next hill.
When he reached the top he was beginning to perspire. He sat down
for a moment to think.
Now that he was close and the moment of contact was so near he
could almost touch it, his mind began to function with a cold,
comforting clarity. It was time to make a plan. His target was the
ship, yes, but he would have to proceed on the assumption that they
knew he was coming. They would have some kind of warning
system, and a variety of weapons. But for the time being he held the
ace.
He grinned cheerlessly to himself and headed for the next rise.
On the other side of this one there was a long flat space, scrub-
bushed and empty, and then the last hill, the steep one, began. He
went forward across the open space in broad daylight. He felt like he
was walking into the mouth of a primed cannon. In effect, he was.
It was in among a clump of pines, silent and green, that the thing
fell to the ground near him. He froze, momentarily panic-stricken, his
hand to his belt. The fallen thing lay on the ground a few inches
from his right hand, stiff and unmoving, dark among the leaves.
He relaxed slightly.
It was only a bird.
A dead bird. He stared at it for a long while, motionless. Out of the
trees above him a dead bird had fallen.
Coincidence?
Or were they now turning on the power?
He lay flat on the ground. They knew where he was and they did not
like it. They had fired on him. He did not know whether the thing
that killed the bird had missed him, or whether it had hit him too
and his incredible immunity had protected him. Perhaps they had
already fired on him with the other gun, the one from the satellite.
He did not know that either. But in front of him lay the dead bird.
And now, if he tripped another electronic eye, they would probably
come out in person.
All for the best. He peered intently through the trees up the hill,
searching for some sign of buildings. If he could get to the edge of a
clearing, could see, he would stand a better chance. But there was
nothing but bushes, the bare brown shafts of trees. Now that they
knew where he was, he was deeply thankful that he'd had the sense
to bring the gun.
He moved forward on his hands and knees, watching, listening,
praying that he didn't trip another eye.
The bushes crackled around him. The wind, dammit.
He stopped and listened, heard his heart beating in his throat. He
decided he could crawl just as well with one hand, so he took out
the gun. It was at that moment that he saw the first Faktor.
An instant silhouette through the trees ahead, moving silently
toward him. They were coming.

He dropped to his stomach, crawled with a cold silent slide into the
nearest bush clump. Although they probably knew to the foot where
he was, he had to lie still.
In a brief, brutal flash of reproach and disgust, he realized what an
idiot he'd been to come out here alone.
But there was no helping that now. He moved down behind a fallen
log, laid the barrel of the .45 on the trunk and sighted through the
leaves.
Now he could hear them. They were small, but sloppy. Maybe they
didn't care. That didn't figure. But by now they had undoubtedly
understood his immunity, were coming to kill him in the bloody ways
of Earth.
He had no way of knowing that the Faktors had been terrified to
realize that a Galactic was approaching, but immensely relieved to
see that the Galactic was afoot. To the Faktors, Web was one of two
things: a hybrid, or a stranded Galactic. For no agent would ever
approach on foot, not in his right mind. Short of a force field, no
armor known will stop a high velocity missile. And a Galactic on foot
could not have that.
The killing of a Galactic was a rare thing, a delectable thing. Seven
Faktors converged on Web.
He let them come in very close, counting them and noting their
positions, before he fired. When the nearest man was ten yards
away, crawling toward Web at an angle, the white round eyes looked
past him. In the last second he saw that they were circling the
wrong spot. They had not expected his sideward movement. He
fired.
The heavy police bullet caught the Faktor in the head. He died
where he lay, instantly. There were swift, rising, horribly frightened
screams from the bushes around him.
Web rolled back from the log, crawled around to the other side of
the tree. The god-awful things were whimpering.
He peered furtively around the tree looking for another shot while
the shooting was good, wondering how in hell they'd ever gotten the
nerve to come in after him. And then he looked at the body of the
alien he'd killed, saw the small brown bomb in his hand, and knew.
They'd never intended to get in close. They probably hadn't even
expected him to be armed.
He grinned viciously, turning his head the while to look for a way
out.
In that instant he saw another alien move. He fired.
The shot went home. There were more screams.
Good God, he said, almost aloud, shocked. He did not fire again, the
fear of the things was revolting. He wanted to get out.
He started to move, but they located him. The first bomb hit on the
other side of the tree, blew with a white blinding flash, a thin,
screaming, ripping explosion.
The tree saved him. He fell flat, tried to crawl away. Two more
bombs let go on the other side of the tree, spattered among the
bushes and leaves, cut the tree in half. The tree fell in the direction
of another bomb, the top of it was blown away. In frantic
desperation, the Faktors were giving it everything they had.
There was a tense moment of silence. Web started to rise. He had to
get away. He fired again and again into the woods around him, rose
and started to run, hoping that the shooting would keep the aliens
flat, that some of them at least had died of fear and that he could
outrun them. He made it as far as another fallen log before the next
bomb let go, giving him a great crunching shove in his back. He fell
face down over the log.
Oh hell, he said painfully, oh hell oh hell oh hell. A bomb fell near
him, and another, and he turned to rise and fire back just once
more, swearing, his flesh rising to greet the one last killing
explosion, and damn it all, he was going to die.
A huge fist hit him squarely between the eyes. He fell over
backwards.
And there was dark, blessed silence.

The doors opened automatically when Prule pushed the right button.
Three hundred and twelve young girls and two hundred and
fourteen young men, all of them the cream of Earth's children and
most of them mother-naked, peered out cautiously, furtively, into the
gathering dusk. One made a move, then another. A rather brazen
young woman, nude, walked right out into the center of the camp.
And then they all emerged, wide-eyed and taut, looking for the
Faktors.
"All gone," said Kunklin, waving his hands expressively. But since his
suit was recharged and working, nobody saw him.
They did not see the Faktors either. They began to gather and talk
with each other, some dangerously close to shock, some excitedly
none the worse for wear. Most of the women were recovered so far
as to return to modesty, began to search for covering.
This did not please Kunklin at all. He was tempted to push the
button again and close all the doors, thereby making all clothing
unavailable, but—after a thoughtful look at Prule—he let it go. It had
been an extraordinary sight, a delectable sight, and his opinion of
the virtues of Earth was skyrocketing.
Right then and there Kunklin decided the spot for his next vacation.
And now at last, as they watched, the men and the girls began to
leave. It was growing dark and quite cold and they could not stay
here. One by one, in varying degrees of undress, they strode off
down the mountain. The sensation they created in Alford was
nothing next to the sensation they created the next day, in
newspapers the world over.
Kunklin watched them go with mixed torture and delight.
Prule brought him back to the next order of business.
"The Earthman," he said gloomily.
"Um?"
"The man from the satellite. Where is he?"
"Um," said Kunklin, sobering. "Where is he indeed?"
Prule pointed a lean finger at the near woods.
"There were explosions going on over there when we flew down. I
suppose—" he fixed his eyes reproachfully on Kunklin—"they
bombed him."
Kunklin shrugged. "The man came all the way up here. Really. You
know, you have to admire these people, in more ways than one. I—"
He broke off.
For out of the woods, stumbling, holding his head in one hand and
his colt .45 in the other, came the great battered figure of Web
Hilton. He was scarred and bloody, one eye was closed and he
walked with a heavy limp, but he was walking at least, and Kunklin
brightened.
"Well by Jupiter, he made it!"
Prule smiled happily.
"We must have just got here in time. The Faktors were probably
bombing him when they disappeared."
"Yes, yes. Well, well, well." Kunklin fussed with a knob, turned off his
bender and switched on the translator. "I suppose, now that it's all
over, we owe this fellow an explanation. Lord, man, we owe him
more than that. He's one of us!" He started walking quickly toward
Web. "Ho! Hey! You there!"
Web stopped, peered confusedly through bleary eyes at the
incredible figures on the mountain side before him. His gun was in
his hand, but he had forgotten it. He had not yet collected himself
and there was an awful ringing in his head.
Kunklin and Prule surrounded him, babbling away cheerfully, set him
down and gave him first aid. In an astonishingly short time he was
feeling well again and the Galactics did their best to bring him up to
date on what had occurred, being careful to praise his undeniable
courage in the face of such odds. They admitted to using him as
decoy, but told him nothing about the recording business. They saw
no reason to tell this boy that he had, during the course of recent
events, died twice. No telling how he would react. Although really,
since he was atom for atom identical with the original Web Hilton,
what difference did it make?
"—and so we finally found a Faktor with some strength of will—had
to inject the man as he came aboard—then came out here and
eliminated the rest of them."
Web stared dazedly around at the empty buildings.
"All gone?"
"Completely." Kunklin grinned. "We used the same device on them
that they used on your people. We thought it only fitting. Quite a
weapon. Used to be the most dangerous weapon in this part of the
universe until we found immunity. You could wipe out whole planets
without a single leaf being harmed—"
"Yes, yes," said Prule, "but the job is ended. Thank you my friend.
You have been of great help. Any time you need us. Kunklin?"
"What?" said Kunklin, straightening. "You mean leave him here? Well
really, Prule, that's hardly—" And then his whole face brightened. He
clapped Web heavily on the back. "Why Prule, this boy's a Galactic!
After all he's done for us, the least we can do is take him back with
us"—Prule jumped—"to headquarters, at least, and introduce him
around. Why, the boy has a heritage! You can see that from the way
he held up his end. Oh yes, yes, we'll have to take him back."
Web looked up blearily, beginning to understand.
"Back where?"
But Kunklin reached down and took him by the arm, and began
leading him toward the ship. He explained, as painlessly as he could,
the fact of Web's Galactic parentage. He did not say that it was
Web's father—which, for biological reasons, it had to be—but only
that some ancestor, somewhere along the line, had been
extraterrestrial.
And while Web was downing that, and Prule was protesting, Kunklin
spoke gaily on.
"You'll need time, my boy, won't you, before you come along with
us? You'll need time, eh?"
"I have to see Dundon—"
"Of course, of course," Kunklin chuckled, "take all the time you want.
Take weeks, take months. And in the meantime," he grinned toward
Prule, in whom just now a great light was dawning—"in the
meantime Prule and I will wander the byroads of your lovely planet.
Eh, Prule? A vacation!"
And in a mood of genial lechery—for Earthman, Galactic, Faktor, this
one thing is constant—the three men climbed into the ship, and
then, the sky.

Ivy Jean Thompson, to complete the story in the coldest of truth,


never set eyes on Web Hilton in her life. And if she had, it would
have made little difference, for the fact of the matter is that Ivy Jean
Thompson had had quite enough of men. Any kind of men. The
disappearance of the Faktors had occurred, coincidentally, at the last
possible moment for the saving of Ivy's virtue. It was,
understandably, an unnerving experience.
She opened her eyes to find nobody there. She left the camp firmly
convinced that there should never be anybody there. She retired to
a small town in north Jersey where she became a particularly
grouchy librarian spinster, the last of all the casualties in the case of
the Blood Brother.
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