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Foreword
This volume on Brain Banking in Neurologic and Psychiatric Diseases in the Handbook of Clinical Neurology series is
the first ever comprehensive book on this topic. Postmortem studies of the human brain provide essential information
that cannot be obtained by in vivo studies in humans or through experimental models in animals. Animal models are
generally models for the symptoms of a neuropsychiatric disorder, rather than a representation of the complete disease.
Moreover, certain human conditions such as suicide have no good animal models. Finally, postmortem tissue is needed
to validate findings in animal models.
A brain bank is a complex organization that provides the international research community with high-quality, well-
characterized, and neuroanatomically well-defined postmortem brain samples of neurologic and psychiatric disorders
and their appropriate controls. Brain banks are necessary, since neurologic and psychiatric patients tend not to die in a
teaching hospital but at home or in nursing homes, where there is no research tradition. Moreover, pathologists do not
usually conduct postmortem examinations on healthy patients without brain disorders, even though the brains from
these subjects are extremely important for use as controls in research projects. Brain banks need staff with a variety
of different competencies, including trained personnel to interact with grieving families, administrative staff to deal
with the database, and neuropathologists and scientific staff to process and disseminate the brain samples.
All aspects of the organization of a brain bank are described extensively in the different chapters of this book, begin-
ning with a description of how donors are obtained, preferably by means of an antemortem donor program. The donors
and their relatives have to be informed, well in advance, about what the procedure entails exactly, and all the necessary
paper work has to be done in advance so that the postmortem time is as short as possible. Alternative strategies for
obtaining brain donations through medicolegal postmortems are also discussed in the volume, as well as ways to obtain
rare cases such as through the Autism BrainNet, a network of brain collection sites in different places in the United
States and Britain.
A thorough characterization of postmortem tissue requires that a comprehensive clinical investigation is conducted
and complete documentation of the patient’s disorder and therapies is obtained. Toxicologic analysis can be extremely
useful. Dissection of a fresh brain according to anatomic borders is not generally part of the neuropathologist’s routine
and therefore requires special training for a neuropathologist working in a brain bank. A systematic and professional
neuropathologic investigation following a standardized protocol for both cases and controls is crucial. Chapters in this
volume indicate that about 20% of the clinical neurologic diagnoses, despite being made in first-rate clinics, have to be
revised or require an extra diagnosis after a complete and thorough neuropathologic review. The neuropathologic
examination is also needed to indicate the stage of the disease, such as the Braak stages for Alzheimer disease. In addi-
tion, accurate clinical and neuropathologic information should ensure that tissue that is, unknowingly, infected with, for
example, prions or human immunodeficiency virus (HIV) is not sent out to research groups. Neurochemical markers
are reviewed in terms of their ability to assess the quality of postmortem brain tissue.
Samples from patients have to be compared to those of controls that are matched for as many of the known con-
founding factors as possible, such as genetic background, systemic diseases, duration and gravity of illness, medicines
and addictive compounds used, age, gender, circadian and seasonal fluctuations, lateralization, agonal state, freezing or
fixation procedures, and storage time. Consequently, brain banks should have a large number of controls available.
Samples should be stored and distributed to the international field of neuroscientists that have open access to the facil-
ity, and the feasibility and quality of their studies should be reviewed and guaranteed by an independent committee.
Brain banking should follow ethical rules such as those described in the code of conduct of the BrainNet Europe
consortium. Fundamental topics that are discussed in the volume include the rights of the persons donating tissue, the
obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality,
protection of personal data, collections of human biologic material and their management, and transparency and
accountability within the organization of a brain bank.
viii FOREWORD
An organization as complex as a brain bank has additional requirements related to information-technology (IT)
infrastructure and database management. A practical guide for designing and implementing an IT system for brain
banking is included in the volume, as also are examples for collecting, managing, and distributing data. A brain bank
is faced with significant costs – while funding tends to come from research and facility grants and donations, these are
all irregular, uncertain, and cover costs for only a fixed period of time. Thus, it is advisable to have a business plan that
identifies the interests of the stakeholders and addresses the implementation of cost efficiency and cost recovery
systems.
This volume also provides useful information on cutting-edge techniques that can be applied to human postmortem
material, such as novel genomic, proteomic, lipidomic, and epigenetic techniques, laser microdissection in combina-
tion with gene expression profiling, novel cell isolation techniques, postmortem cell cultures, donor-derived induced
pluripotent stem cells, tissue-clearing methodologies to study three-dimensional brain circuits, electrophysiologic
recordings in both surgically derived brain tissue and autopsy material, studies that combine postmortem magnetic
resonance imaging and histopathology, and human brain mapping integrating results of quantitative cyto- and
receptor-architectonic techniques.
We were very fortunate to have as volume editors two distinguished scholars who are well versed in brain banking:
Ingeborg Huitinga, Director of the Netherlands Brain Bank, in the Netherlands Institute for Neuroscience, Amsterdam,
and Maree J. Webster, Executive Director of the Stanley Medical Research Institute, Kensington, Maryland. They have
assembled an excellent international and multidisciplinary group of experts and guided them firmly to create this com-
prehensive book. We are very grateful to them and to all the contributors.
As always, it is a pleasure to thank Elsevier, our publisher – and in particular Michael Parkinson in Scotland,
and Mara Conner, Nikki Levy, and Kristi Anderson in San Diego – for their unfailing and expert assistance in the
development and production of this volume.
Michael J. Aminoff
François Boller
Dick F. Swaab
Preface
Brain banks collect, store, and disseminate postmortem human brain tissue to facilitate research into the normal
function as well as disease etiology of the human central nervous system. Human brains have been essential to expose
the pathologic hallmarks of neurologic diseases such as Alzheimer and Parkinson diseases; postmortem brains from
patients with psychiatric diseases have been less studied. The human brain has recently become a major focus for
neuroscience research worldwide, as illustrated by the billion-euro European Union Human Brain Project (https://
www.humanbrainproject.eu/) and the 100-million-dollar BRAIN initiative to map the human brain (http://blog.
brainfacts.org/2013/04/barack-obama-neuroscientist-in-chief/#.VNswYfmG8mk). These initiatives highlight the
diverse scientific approaches necessary to link structure and chemicals to behavior and cognition.
Sophisticated scanning techniques identified alterations in size, activity, and connectivity in neurologic and
psychiatric brains, but these now need to be mapped at the cellular and molecular level. New powerful (epi-) genomic,
proteomic, and lipidomic expression techniques are now available to identify molecular changes related to brain dis-
eases. Abnormalities and potential therapeutic targets identified in animal models of neurologic and psychiatric
disorders as well as targets identified by genomewide association studies all need to be validated in human brain tissue.
These approaches require substantial numbers of well-characterized, high-quality human brains from patients with
neurologic and psychiatric diseases as well as unaffected control brains. It will be the task of professional brain banks
that are well organized, financially sustainable, and readily accessible to the research community to provide such high-
quality samples. As more and more cutting-edge technologies are evolving and being adapted for postmortem brain
tissue, the demand for such tissue is expanding and leading to many initiatives worldwide to start or professionalize
brain banks.
Thus, we believe it is an important time to produce a volume of the Handbook of Clinical Neurology that focuses on
brain banking for both neurologic and psychiatric disorders. We were honored to be invited to edit the volume and to
have the opportunity, in turn, to invite our colleagues in the various specialties within brain banking to contribute their
expertise. The volume covers the full range of issues that are important to designing, implementing, and maintaining a
successful brain bank for neurologic and psychiatric disorders. Whether starting a new initiative to collect postmortem
brains or attempting to upgrade the protocols and management of an existing brain bank, readers will find valuable
information and guidance within these chapters.
The volume is divided into seven sections that provide overviews and discussion of all aspects of brain banking and
include both practical guides to implementing procedures specific to brain banks, such as the necessary IT infrastruc-
ture and means of obtaining financial sustainability, to scientific papers describing research conducted on postmortem
human brain samples. The first and second sections describe ways to organize programs to procure donors and provide
examples of brain bank networks that can maximize the number of donations. The third section outlines a number of
ethical and legal aspects as well as financial issues that need to be considered when establishing donor programs and
when establishing protocols for managing and distributing the tissue as an open resource to scientists. The fourth and
fifth sections describe the brain dissection, tissue-processing, and quality control protocols that must be considered and
standardized for the needs of each brain-banking initiative. The sixth section considers various aspects of how the clin-
ical donor data, the neuropathologic data, and the data derived from the research on each case are derived, stored, man-
aged, and distributed. The seventh and final section provides some beautiful examples of cutting-edge techniques that
have recently been applied to postmortem human brain tissue. These studies reveal the extent of the fascinating data that
can be derived from high-quality, well-characterized postmortem samples and provide much-needed insight into the
structure and function of the human brain.
We believe that readers will find this volume of the Handbook of Clinical Neurology to be a valuable contribution to
the existing literature by bringing together expertise on all aspects of organizing, managing, and implementing a brain
bank. We sincerely thank all the contributors for helping to bring this volume to fruition.
Ingeborg Huitinga
Maree J. Webster
This page intentionally left blank
Contributors
I. Alafuzoff S. Berretta
Department of Immunology, Genetics and Pathology, Harvard Brain Tissue Resource Center and Translational
Uppsala University; Department of Clinical and Surgical Neuroscience Laboratory, McLean Hospital, Belmont;
Pathology, Uppsala University Hospital and Rudbeck and Department of Psychiatry and Program in
Laboratory, Uppsala, Sweden Neuroscience, Harvard Medical School, Boston, MA,
United States
D.G. Amaral
The MIND Institute, University of California at Davis, J.-P. Brion
Sacramento, CA, United States Laboratory of Histology, Neuroanatomy and
Neuropathology, ULB Neuroscience Institute,
M.P. Anderson Universite Libre de Bruxelles, Brussels, Belgium
Department of Neurology and Pathology, Beth Israel
Deaconess Medical Center, Harvard Medical School, S. Chance
Boston, MA, United States Nuffield Department of Clinical Neurosciences,
Academic Unit of Neuropathology, John Radcliffe
K. Ando Hospital, University of Oxford, Oxford,
Laboratory of Histology, Neuroanatomy and United Kingdom
Neuropathology, ULB Neuroscience Institute,
Universite Libre de Bruxelles, Brussels, Belgium; and E.P. Cortes Ramirez
Laboratoire de Neuropathologie Escourolle, H^ opital de Taub Institute for Research on Alzheimer’s Disease and
la Pitie-Salp^etrière, Paris, France the Aging Brain, Columbia University Medical Center
and New York Brain Bank, Children’s Hospital,
O. Ansorge New York, NY, United States
Nuffield Department of Clinical Neurosciences,
Academic Unit of Neuropathology, John Radcliffe G.M. de Lange
Hospital, University of Oxford, Oxford, Brain Center Rudolf Magnus, Utrecht, The Netherlands
United Kingdom
C. Duyckaerts
R.J. Baldessarini Laboratoire de Neuropathologie Escourolle, H^opital de
Department of Psychiatry, Harvard Medical School, la Pitie-Salp^etrière, Paris, France
Boston and International Consortium for Psychotic and
Bipolar Disorders Research, McLean Hospital, Belmont, I. Ferrer
MA, United States Pathologic Anatomy Service, Institute of
Neuropathology, Bellvitge University Hospital;
A.-M. Bao Department of Pathology and Experimental
Department of Neurobiology, Key Laboratory of Medical Therapeutics, Faculty of Medicine, University of
Neurobiology of Ministry of Health of China; Zhejiang Barcelona; and Network Center of Biomedical Research
Province Key Laboratory of Neurobiology, Zhejiang on Neurodegenerative Diseases, Institute Carlos III;
University School of Medicine, Hangzhou, China Hospitalet de Llobregat, Llobregat, Spain
xii CONTRIBUTORS
M. Freund C.E. Keller
National Institute of Mental Health, Rockville, MD, Department of Pathology, Henry Ford Hospital, Detroit,
United States MI, United States
3. Autism BrainNet: a network of postmortem brain banks established to facilitate autism research
D.G. Amaral, M.P. Anderson, O. Ansorge, S. Chance, C. Hare, P.R. Hof, M. Miller,
I. Nagakura, J. Pickett, C. Schumann, and C. Tamminga (Sacramento, Boston, New York and Dallas,
United States, and Oxford, United Kingdom) 31
SECTION III Ethical aspects of brain banking and management of brain banks
8. The New York Brain Bank of Columbia University: practical highlights of 35 years of experience
E.P. Cortes Ramirez, C.E. Keller, and J.P. Vonsattel (New York and Detroit, United States) 105
10. Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain
and in neurodegenerative disorders
I. Alafuzoff (Uppsala, Sweden) 131
xvi CONTENTS
11. Brain donation at autopsy: clinical characterization and toxicologic analyses
M.I. Mighdoll and T.M. Hyde (Baltimore, United States) 143
SECTION VI Brain donor data: clinical, genetic, radiologic, and research data storage and mining
14. What can we learn about brain donors? Use of clinical information in human
postmortem brain research
K. Sullivan, H. Pantazopoulos, E. Liebson, T.-U.W. Woo, R.J. Baldessarini, J. Hedreen, and S. Berretta
(Belmont and Boston, United States) 181
15. The art of matching brain tissue from patients and controls for postmortem research
A.-M. Bao and D.F. Swaab (Hangzhou, China and Amsterdam, The Netherlands) 197
SECTION VII Human brain tissue analyses: old and new techniques
16. Considerations for optimal use of postmortem human brains for molecular psychiatry: lessons
from schizophrenia
C.S. Weickert, D.A. Rothmond, and T.D. Purves-Tyson (Sydney, Australia) 221
18. Laser microdissection and gene expression profiling in the human postmortem brain
K.-C. Sonntag and T.-U.W. Woo (Belmont and Boston, United States) 263
19. Purification of cells from fresh human brain tissue: primary human glial cells
M.R. Mizee, M. van der Poel, and I. Huitinga (Amsterdam, The Netherlands) 273
21. 3D imaging in the postmortem human brain with CLARITY and CUBIC
K. Ando, Q. Laborde, J.-P. Brion, and C. Duyckaerts (Brussels, Belgium and Paris, France) 303
22. Neuronal life after death: electrophysiologic recordings from neurons in adult human brain tissue
obtained through surgical resection or postmortem
I. Kramvis, H.D. Mansvelder, and R.M. Meredith (Amsterdam, The Netherlands) 319
Index 419
Section I
Chapter 1
Abstract
The Netherlands Brain Bank (NBB) performs rapid autopsies of donors who gave written informed
consent during life for the use of their brain tissue and medical files for research. The NBB initiated
the Netherlands Brain Bank for Psychiatry (NBB-Psy), a prospective donor program for psychiatric
diseases. NBB-Psy wants to expand the tissue collections in order to provide a strong incentive to increase
research in psychiatry. The ultimate goal of NBB-Psy is to reduce the burden of psychiatric disorders for
patients, their families, and for society as a whole. NBB-Psy consists of an antemortem and postmortem
donor program. This chapter focuses on the design of NBB-Psy and the antemortem donor program, where
patients and relatives are actively informed on the possibility to become a brain donor. Since the initiation
of NBB-Psy, the number of registered donors with a psychiatric diagnosis has increased from 149 in 2010
to 1018 in May 2016.
INTRODUCTION
disorders was 5.7 billion euros (www.nationaalkompas.nl/
Psychiatric disorders are prevalent and contribute signif- zorg/huidige-kosten/#kostennaarsector). In order to lower
icantly to disease and economic burden worldwide. The morbidity and the economic burden, there is an urgent need
World Health Organization reported an estimated life- for improved treatment strategies which requires a better
time prevalence of any Diagnostic and Statistical understanding of the underlying etiology and pathophy-
Manual of Mental Disorders, fourth edition (DSM-IV: siology of psychiatric disorders.
American Psychiatric Association, 1994) disorder rang- In the past decades, brain imaging, genetic, and ani-
ing from 12% in Nigeria to 47.4% in the United States mal studies have improved our understanding of psychi-
(Kessler et al., 2007). In the Netherlands, the lifetime atric disorders. For example, imaging studies have
prevalence of axis I DSM-IV disorders is 42.7% identified alterations in volume, connectivity, and activ-
(de Graaf et al., 2011). ity of certain brain areas in psychiatric disorders. How-
Disorders of the brain are the largest contributor to the ever, these methods cannot elucidate the molecular and
morbidity burden as measured by disability-adjusted cellular changes that may occur in the human brain.
life-years in the European Union (38.2%) (Wittchen et al., While genetic studies using peripheral blood are able
2011). These disorders are also very costly. In 2010 the to uncover genes that are associated with psychiatric
European economic burden was estimated to be 798 billion disorders, this genetic blueprint does not necessarily
euros, of which 302.4 billion euros were spent on psychi- reflect the gene expression or functional changes in the
atric disorders (Olesen et al., 2011). In the Netherlands brain (Lewis, 2002; Seifuddin et al., 2013). Rodent
alone the total healthcare costs for 2011 were almost models of psychiatric disorders, although helpful in
90 billion euros, of which the total cost for psychiatric modeling psychiatric symptoms such as anxiety, have
*Correspondence to: Marleen C. Rademaker, Department of Psychiatry, University Medical Center, Utrecht, The Netherlands.
E-mail: M.C.Rademaker-6@umcutrecht.nl
4 M.C. RADEMAKER ET AL.
limited validity when modeling symptoms such as hallu-
cinations and suicidal thoughts that cannot be simulated
in animal models (Nestler and Hyman, 2010). Therefore,
postmortem research of the human brain is a crucial
additional strategy to advance our understanding of
the mechanisms underlying psychiatric disorders. Post-
mortem research of psychiatric disorders can contribute
to new ways of conceptualizing these disorders, for exam-
ple, by investigating whether symptoms shared by differ-
ent psychiatric disorders, such as withdrawal behaviour in
autism, schizophrenia, and depression, have the same neu-
ropathologic underpinnings. Furthermore, postmortem
research on fresh glial cells, obtained immediately after
brain dissection, can be used to study the impact of envi-
ronmental risk factors in vitro, and may point towards new
pathways of interventions. Postmortem studies may also
facilitate the development and validation of peripheral
markers that may reveal the molecular and cellular under-
pinnings of psychiatric disorders.
Unfortunately, there are only a limited number of
international brain banks that collect postmortem psychi-
atric brains for research purposes (Deep-Soboslay et al., Fig. 1.1. Total number of brain autopsies (1985–2015). AD,
Alzheimer disease; CO, control; FTLD/Tau, frontotemporal
2011). Therefore, the Netherlands Brain Bank (NBB) of
dementia/Tau; MS, multiple sclerosis; Other dem, other
the Netherlands Institute for Neuroscience, in collabora-
dementia; PD, Parkinson disease and related disorders; PSP,
tion with five university medical centers, initiated the progressive supranuclear palsy; Psych, psychiatric disorders;
Netherlands Brain Bank for Psychiatry (NBB-Psy) as Other, other diagnoses; PA not ready, neuropathologic report
part of the NBB. This 5-year program, that started in is not ready yet.
September 2012, oversees a prospective donor program
for psychiatric brain diseases to expand the tissue collec- with multiple sclerosis, and 1260 controls without brain
tion for the purpose of stimulating research in psychiatric diseases. The NBB has also provided tissue from approx-
disorders. With NBB-Psy, we aimed to stimulate post- imately 1200 other diseases, including brain tissue from
mortem psychiatric research by increasing the amount 119 psychiatric cases (depression, bipolar disorder,
of excellent-quality psychiatric human brain tissue and schizophrenia) to 700 research projects all over the
that is available for research. Initially our target was to world (data April 2016). This has resulted in more than
perform 500 brain autopsies of seven psychiatric brain 1700 scientific papers (www.brainbank.nl/research/
disorders in 10 years. The ultimate goal is to reduce publications/). The NBB has more than 3800 registered
the burden of psychiatric disorders for patients, their living donors (Fig. 1.2). Eighty-five percent of the regis-
families, and for society as a whole. tered donors with a psychiatric disorder registered them-
selves as brain donor in the last 2.5 years, after the
The Netherlands Brain Bank initiation of NBB-Psy.
Fig. 1.3. The organization of Netherlands Brain Bank (NBB) for Psychiatry. KNAW, Royal Netherlands Academy of Arts and Sciences;
e-NBB, electronic Netherlands Brain Bank; IT, information technology; MC, medical center; iPSC, induced pluripotent stem cell.
Fig. 1.4. Schematic overview of the components of Netherlands Brain Bank (NBB) for Psychiatry. DSM, Diagnostic and Statis-
tical Manual; MINI-Plus, Mini-International Neuropsychiatric Interview-Plus; eNBB, electronic Netherlands Brain Bank.
Based on these criteria the NBB-Psy selected schizophre- but signed up with one of the seven NBB-Psy disorders,
nia and other psychotic-related diagnoses, bipolar disor- the NBB asked permission to verify their diagnosis
der, major depressive disorder, obsessive-compulsive by requesting the general practitioner to send the most
disorder and body dysmorphic disorder, posttraumatic recent DSM classification from the treating psychiatrist.
stress disorder (PTSD), autism spectrum disorder (ASD), Also, the RA invited every noncohort psychiatric donor
and attention-deficit hyperactivity disorder (ADHD) to to cooperate with a short psychiatric interview, the Mini-
recruit. International Neuropsychiatric Interview (MINI: section
Phenotyping of noncohort NBB-Psy donors, below).
INCLUSION AND EXCLUSION CRITERIA FOR DONOR The RA invited every noncohort control subject to also
REGISTRATION INNBB-PSY participate in the MINI interview (see below), to confirm
the absence of psychopathology. Figure 1.5 shows a flow-
All participants in the psychiatric cohort studies that col-
chart of the NBB’s donor registration process.
laborate with NBB-Psy were eligible to sign up as a
brain donor, including patients, healthy relatives, and
PUBLIC AWARENESS
control subjects. Since cohort participants were already
extensively phenotyped, the cohort participants who Organ donation and body donation for education and
signed up as prospective brain donors were accepted research purposes are regular forms of donation in the
without further verification of their psychiatric classifi- Netherlands. In contrast, brain donation for scientific
cation, or, in case of a healthy subject, the absence of a research is still largely unknown to the majority of the
classification. When people were not in a clinical cohort Dutch population. Over 90 percent of the people
8 M.C. RADEMAKER ET AL.
Fig. 1.5. Flowchart donor registrations for Netherlands Brain Bank (NBB) for Psychiatry. DSM, Diagnostic and Statistical
Manual; MINI +, Mini-International Neuropsychiatric Interview-Plus.
approached by NBB-Psy were not aware of the existence We Need Brains (www.wehebbenhersensnodig.nl),
of the NBB. In our experience, priming the public by the Dutch population was petitioned to consider
repeatedly presenting information on brain donation is registering as brain donors. The campaign raised media
crucial for creating public awareness on the possibility attention on television, radio, and in (online) written
of brain donation. The NBB-Psy increased awareness press. Within the first month of the campaign week,
in a number of ways: almost 1000 people contacted the NBB willing to
consider brain donation.
1. The NBB-Psy program has a website, www.nhb-
psy.nl, with extensive information on the necessity
of psychiatric brains for research but also practical DONOR RECRUITMENT
information on how to become a brain donor. The
PSYCHIATRIC RESEARCH COHORTS
site also includes a page of frequently asked ques-
tions (FAQs) and informational animations. The Netherlands is well known for its large psychiatric
2. NBB-Psy obtained national publicity through news- research cohorts (Table 1.1). One of the main donor
paper articles, and through interviews on national recruitment activities of NBB-Psy was to inform all par-
radio and television. An overview of the articles ticipants individually in these cohorts about the possibil-
and links to radio programs can be found on the ity of becoming a brain donor for scientific research.
website. Table 1.1 shows an overview of the participating cohorts.
3. The NBB-Psy developed informational films, which In these cohorts, patients, as well as family members and
are promoted at every possible occasion, and which control subjects, were extensively phenotyped and often
can be viewed on the NBB YouTube channel as well monitored for several years. Depending on the cohort,
as on the website. information from various tests and interviews, including
4. NBB-Psy used social media, with an active Twitter the Structured Clinical Interview for DSM-IV (SCID),
(@NHBPsy) and Facebook account. Composite International Diagnostic Interview, Inven-
5. A well-known Dutch author, Myrthe van der Meer, tory of Depressive Symptoms, Borderline Personality
diagnosed with bipolar disorder and Asperger syn- Questionnaire, Beck Anxiety Inventory, Mood and
drome, became a brain donor and an active ambas- Anxiety Symptom Questionnaire, Positive and Negative
sador for NBB-Psy. Syndrome Scale, Yale-Brown Obsessive Compulsive
6. NBB-Psy launched a national campaign on the impor- Scale, Autism Diagnostic Interview – Revised, and
tance of brain donation for research on psychiatric Autism Diagnostic Observation Schedule were avail-
disorders in March 2016. With radio commercials, able. In addition, data from structural and/or functional
(digital) posters at train stations and a special website, magnetic resonance imaging (fMRI), single-photon
Another random document with
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Clinton was not sorry to hear this announcement of his afternoon’s
work; for though he was not a lazy boy, it really seemed to him, that
just then a ride to the Cross-Roads would be quite as pleasant as an
afternoon spent at work in the field. So Fanny was soon harnessed
into the wagon, and Clinton started on his errand.
Mr. Fletcher was a trader, who kept a store at the Cross-Roads,—
a place where two of the main highways of the county cross each
other at right angles, thus ✛.[2] Quite a thrifty little village had sprung
up at this point, boasting, among other things, a school-house, a
church, a post-office, and a “variety store.” It was, in fact, the centre
of life and business for the surrounding dozen miles. Though about
five miles from Mr. Davenport’s house, there was no other store or
church within twice the distance. His family, consequently, had
almost come to regard the Cross-Roads settlement as a part of their
own village, though it was actually situated in another township.
Clinton had not driven half way to his destination, when he
discovered two lads in advance of him, walking the same way he
was going. On coming up with them, he found that they were Oscar
and Jerry, who were out on a gunning excursion,—Oscar having
borrowed a fowling-piece of a young man who lived near Mr.
Preston’s.
“Halloo, Clin, give us a ride,” exclaimed Oscar, as the wagon drew
up to them; and without further ceremony, both boys jumped into the
vehicle.
“Where are you going?” inquired Clinton, as he started the horse.
“O, wherever you please,—we are not at all particular,” replied
Oscar. “Jerry and I have been trying to pop off some birds, this
afternoon, but the little fools won’t stop long enough to let us shoot
them.”
“I’m glad of it,” replied Clinton, dryly.
“Why are you glad?” asked Jerry.
“Because it’s too bad to shoot them,” replied Clinton. “I like to see
and hear them too well, to harm them. If I could have my way, there
shouldn’t be a bird shot, unless they were crows or hawks, or
something of that kind.”
“Pooh,” said Oscar; “I should like to know what birds were made
for, if it wasn’t to be shot. You don’t know what fine sport it is to shoot
them, or you would be as fond of gunning as I am.”
Oscar had probably shot half a dozen poor little birds in the course
of his life, and severely frightened as many more. But he had got the
idea that gunning was a fine, manly amusement, and he already
fancied himself to be quite an accomplished sportsman. And if the
disposition could have made him a successful hunter, he would have
been one; for he wanted to take the life of every bird and squirrel that
he saw. He soon found, however, that it was easier to fire than to hit;
and in most of his excursions, his powder-flask was emptied much
faster than his game-bag was filled.
The boys continued their conversation, and soon reached the
Cross-Roads. Driving the wagon up to Mr. Fletcher’s store, Clinton
alighted, but on trying the door, he found it locked. Mr. Fletcher had
evidently stepped out for a few minutes, and Clinton was about to
hitch the horse to the post, and await his return, when Oscar
proposed driving round to the “Falls,” instead of waiting there.
Clinton at first refused; but Jerry and Oscar both joined in the
request so earnestly, that he soon began to parley and hesitate, and
finally ended by reluctantly yielding to their proposition. He
accordingly jumped into the wagon, and turned the face of Fanny
towards the Falls.
The lake, or pond, which has been before alluded to, has one
outlet,—a little stream which flows away in a south-westerly
direction, finally discharging into a larger river, which finds its way to
the ocean. This little stream, which goes by the simple name of “The
River,” in Brookdale, passes near by the Cross-Roads. About a mile
beyond that village, it comes to a wild, romantic, down-hill place,
where the waters tumble about, and frolic among the rocks, as
though they really enjoyed the sport. This place is called “The Falls,”
the descent of the river here being very marked. It is off from the
common roads, the only way of reaching it being by a “wood-
road,”—a sort of path through the forest, used by the teams in
hauling wood. The very seclusion of the spot, however, made it the
more charming, and it was often resorted to by pleasure parties in
the summer.
The road through the woods being narrow and rough, Clinton
could not drive very swiftly; but he and his companions talked fast
enough to make up for their slow progress. They had not proceeded
very far in this road, when Oscar drew from his pocket a small
package, enveloped in a piece of paper, which he began to unroll
slowly, and with a very knowing and significant look. The contents
proved to be three cigars. Holding them out in his hand, he
exclaimed:—
“How lucky! just one a-piece. Now, boys, for a good smoke. Take
one, Clin; and here, Jerry, is one for you.”
Jerry took the cigar offered, but Clinton shook his head, saying
that he did not smoke.
“You don’t know what you lose, then,” said Oscar. “I’ve smoked
these two or three years, and I couldn’t live without my cigar, now.
You can’t imagine how much pleasure there is in it. Come, just try
this, and see if it isn’t nice.”
“No,” replied Clinton, “I don’t wish to. Father hates tobacco, in
every shape, and he wouldn’t like it if he knew I smoked.”
“But this is all prejudice,” added Oscar. “Smoking never hurt me,
yet, and nobody can make me believe that there is any harm in it. I
felt a little sickish for a few minutes, the first time, but that was
nothing. Come, try it, Clin,” he added, as he drew a match from his
pocket, and lighted his own cigar; “try it—it can’t hurt you,—and
besides, your father needn’t know anything about it.”
“Here goes mine,” said Jerry, as he touched off a match, and
applied the fire to his cigar. “My father wont object, I know, for he
smokes himself like everything; and if he did object, I guess it
wouldn’t make much difference. I don’t intend to be a boy all my life-
time.”
The two young smokers were soon puffing away in good earnest.
Oscar was an old hand at the business, and Jerry had been
practising pretty diligently since his city cousin came to live with him.
Between each whiff, however, they renewed their assaults upon the
good resolution of their comrade; and so skilfully and perseveringly
did they conduct the attack, that Clinton, after a while, began to think
it looked a little unsocial and obstinate to refuse to participate in their
enjoyment. By the time they had reached the Falls, he had
concluded to yield to their wishes. He accordingly drove Fanny into
the water, and unhitched her bridle, that she might drink and cool
herself. The three boys then threw themselves down upon the grass,
beneath a large tree, and prepared to enjoy the scene, and at the
same time repose their limbs. Clinton lighted his cigar,—and now
commenced his first experience in tobacco. He was pleased with the
new sensation; and as he lay upon his back, watching the delicate
wreaths of smoke ascending from his cigar, and listening to Oscar,—
who was spinning out one of his long yarns about a military muster
he once witnessed in Boston,—the time flew by much faster than he
was aware. His cigar had half disappeared, and those of his
companions were nearly used up, when he happened to notice that
the sun was fast declining, and would soon go down behind the tops
of the tall pines on the other side of the stream. Tossing his cigar into
the water, he jumped up, saying:—
“Come, boys, this wont do,—we must be on our way home.”
“What’s your hurry?” inquired Jerry; “it isn’t four o’clock yet.”
“Perhaps it isn’t,” replied Clinton, “but I ought to have been at
home by this time. Come, jump in, and I will turn the horse round.”
The boys got into the wagon, and were soon slowly threading their
way out of the woods. In about half an hour they reached Mr.
Fletcher’s, where Clinton stopped, and got the bags of seed. He had
now a pretty good load, and much of the way being up hill, he did not
get along very fast. Oscar and Jerry talked as fast as usual, but
Clinton looked sober, and did not seem inclined to say much. Indeed,
he hardly spoke to them, from the time they left the store until they
reached the house where Oscar and Jerry lived, when he bade them
good afternoon, and drove on.
The fact was, Clinton was suffering the penalty of his first cigar,
but he did not like to confess it, and this was the reason why he said
nothing. Soon after he started from the Falls, he began to experience
a sinking, nauseating feeling in his stomach, and every jolt and jerk
of the wagon seemed to increase it. He concealed his feelings from
Oscar and Jerry, as much as he could, and after they had alighted,
he hurried home as fast as possible.
It was past six o’clock when Clinton drove into the yard at home.
His father, who had begun to feel anxious at his long absence, had
come in from the field, and on seeing Clinton, he called out to him,
somewhat sharply,
“Where have you been all the afternoon, Clinton? I’ve been waiting
for you more than two hours.”
“Mr. Fletcher wasn’t there, and I had to wait for him,” replied
Clinton. “Besides, it was so warm I thought I wouldn’t drive very fast.”
Ah, Clinton, have you forgotten that it is a falsehood to tell but half
the truth?
Clinton had begun to unharness the horse, when he became so
faint and dizzy that he was obliged to stop; and before he could get
into the house, he began to vomit. His father, hearing the noise, ran
to his aid, and led him into the house. The pale, deathly look of
Clinton, as his father assisted him into the sitting-room, was the first
notice his mother received that he was ill. She was somewhat
startled by the suddenness of his entrance, and at first thought that
he had got hurt.
“Mercy on us! what has happened?” was her first exclamation.
“Nothing alarming,” replied Clinton; “I am a little sick at my
stomach—that is all.”
“How long have you been so?” inquired his mother.
“Only a little while,” was the reply. “I haven’t felt very smart for an
hour or two, but just as I got home I began to grow worse, and have
been vomiting.”
“Have you eaten any thing this afternoon?” inquired Mr.
Davenport.
“No, sir,” replied Clinton, “nothing since dinner.”
“I am afraid he has worked too hard lately,” remarked Mrs.
Davenport to her husband. “You have kept him at it pretty steadily for
a week past, and you know he isn’t so rugged as many boys are. I
wouldn’t allow him to work so hard again.”
“He has been working pretty hard, I know,” observed Mr.
Davenport; “but he has never complained before, and I did not
suppose he suffered from it. I don’t think this is anything serious, wife
—he needs a little physic, perhaps, or something of that sort, to
regulate his system.”
While this conversation was taking place, Clinton sat in the
rocking-chair, leaning his head upon his hand. Little Annie stood by
his side, silent and sad, her large, loving eyes looking up
wonderingly at her sick brother. But he did not notice her. He was
thinking very earnestly of something else. His conscience was busily
at work, reproaching him for his conduct during the afternoon. “You
disobeyed your father,” it plainly said, “by going over to the Falls,
when he told you to come right home. You deceived him, after you
got home, by not giving the true reason for your long absence. You
made yourself sick by smoking that cigar, and now you sit still and
hear your parents, in their sympathy and solicitude, attribute your
illness to hard work. O Clinton, you have not only done very wrong,
but you have done it very meanly, too! No wonder you cover up your
face, and dare not meet the eye of your parents.”
Thus was conscience talking. At first, Clinton almost resolved to
confess the whole story of his wrong-doings. “Do it,” said
conscience; but shame whispered, “no, don’t expose yourself—you
will soon feel better, and the whole affair will be forgotten in a day or
two.” The longer he hesitated, between these two advisers, the less
inclined did he feel to make the confession. His father soon went out,
to put up the horse, and his mother set about preparing him a bowl
of thoroughwort tea—her favorite medicine, in all common forms of
sickness. Clinton already began to feel much better, and on the
whole he thought he would say nothing about the adventures of the
afternoon. When his mother brought him the herb tea, he drank it
down as fast as possible, but he could not help making a wry face
over it, for it was not very palatable to his taste. His mother thought
he had better go to bed early, and without eating any supper, and he
complied with her wishes. Just as he was beginning to doze, a
gentle, timid voice awakened him, saying,
“Clinty, you won’t be sick, will you?”
“No, sis,” he answered, and with a parting “good-night,” he fell
asleep—not the sweet, calm sleep to which he was accustomed, but
fitful, troubled dreams, in which the unpleasant events of the
afternoon flitted before him, in an exaggerated and grotesque, but
always sad and reproachful panorama.
FOOTNOTES:
[2] See the Map of Brookdale, p. 14.
CHAPTER IV.
CRIME.