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Abdeslem El Idrissi
Dan McCloskey Editors
Neurobiology
of Autism
Spectrum
Disorders
Neurobiology of Autism Spectrum Disorders
Abdeslem El Idrissi • Dan McCloskey
Editors
Neurobiology of Autism
Spectrum Disorders
Editors
Abdeslem El Idrissi Dan McCloskey
Center for Developmental College of Staten Island
Neuroscience and Department of Biology City University of New York
College of Staten Island New York, NY, USA
City University of New York
New York, NY, USA
Graduate Center
Program Biology-Neuroscience
City University of New York
New York, NY, USA
ISBN 978-3-031-42382-6 ISBN 978-3-031-42383-3 (eBook)

https://doi.org/10.1007/978-3-031-42383-3
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
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Preface
The human brain is a complex self-organizing system which depends on precise

timing of genes, circuits, experiences, and behaviors to function. Through neurodi-
versity, we learn the different ways that the brain can self-organize with varying
degrees of impact on overall brain function. Of the neurodevelopmental disorders
which demonstrate neurodiversity, none are more informative than autism spectrum
disorder (ASD). Understanding ASD and its diverse manifestations not only helps
us to unravel the basic principles underlying the organization and function of the
human brain, but also helps us to find ways to improve the quality of life of those
that are negatively impacted by it.
ASD is a neurodevelopmental condition that affects millions of individuals
worldwide, encompassing a broad range of symptoms and challenges. It can pro-
foundly impact an individual’s social interaction, communication abilities, and sen-
sory processing, often accompanied by repetitive behaviors and restricted interests.
Despite its prevalence and profound impact on individuals and their families, the
underlying mechanisms and causes of ASD remain a subject of intense scientific
investigations and debates.
This book, Neurobiology of Autism Spectrum Disorder, delves deep into the
intricate interplay between genetics, brain structure and function, and environmen-
tal factors that shape the development and expression of ASD. It was designed to
provide a comprehensive overview of the current state of research, synthesizing
findings from various disciplines such as epidemiology, neurobiology, psychology,
genetics, and clinical studies.
Within these pages, we gather the expertise of leading researchers and clinicians
in the field of autism research to present a comprehensive overview of our current
understanding of ASD. We offer a diverse range of perspectives, theories, and
empirical evidence that shed light on the intricate mechanisms underlying this com-
plex disorder. We aim to bridge the gap between cutting-edge research and practical
knowledge, providing a resource that is accessible to both professionals and indi-
viduals seeking to deepen their understanding of autism spectrum disorder.
Throughout this book, we recognize the immense impact that ASD can have on
individuals, families, and communities worldwide. Our ultimate goal is to
v
vi Preface
contribute to the advancement of evidence-based practices that can improve the

lives of individuals on the autism spectrum.
While this book does not claim to provide all the answers, it serves as a valuable
resource for researchers, clinicians, educators, and anyone seeking a deeper under-
standing of the neurobiological foundations of ASD. By synthesizing cutting-edge
research and presenting it in a clear and accessible manner, we hope to inspire fur-
ther investigation and foster collaborative efforts in unraveling the complexities of
this enigmatic condition.
We extend our gratitude to all the authors who have contributed their expertise
and insights to this volume. We would also like to express our appreciation to the
countless individuals and families affected by ASD, whose lived experiences con-
tinually remind us of the importance of our work.
May this book serve as a stepping stone towards greater understanding, compas-
sion, and progress in the field of autism spectrum disorder research.
New York, NY, USA Abdeslem El Idrissi

Dan McCloskey
Contents
1 Dysfunctional Circuit Mechanisms of Sensory Processing

in FXS and ASD: Insights from Mouse Models�� 1
Anubhuti Goel
2
Theory of Mind in Autism �� 23
Bertram O. Ploog
3 Prenatal and Early Life Environmental Stressors: Chemical
Moieties Responsible for the Development of Autism Spectrum
Disorder�� 37
Kanishk Luhach, Poonam Sharma, Niti Sharma, Neerupma Dhiman,
Harsha Kharkwal, and Bhupesh Sharma
4 Animal Models of ASD�� 75
Bruna Lotufo-Denucci
5
Mitochondrial Dysfunction in Autism Spectrum Disorders�� 85
Thiago Nunes, Alexandra Latini, and Joana M. Gaspar
6 The Usability of Mouse Models to Study the Neural Circuity
in Autism Spectrum Disorder: Regulatory Mechanisms of Core
Behavioral Symptoms�� 105
Hiroyuki Arakawa and Yuki Higuchi
7
Seizures in Mouse Models of Autism�� 123
Alison J. Sebold, Alyssa Strassburg, Natalia Avery, Darya Ryndych,
Violeta B. Foss, Preet Sawhney, and Gonzalo H. Otazu
8 Lipid-Related Pathophysiology of ASD�� 145
Kelly Noah and Elaine Tierney
9 Perinatal Insulin-Like Growth Factor as a Risk Factor
for Autism�� 167
Gary Steinman and David Mankuta
vii
viii Contents
10 Prophylactic Treatment of ASD Based on Sleep-Wake Circadian

Rhythm Formation in Infancy to Early Childhood�� 183
Teruhisa Miike, Makiko Toyoura, Kentaro Oniki, Shiro Tonooka,
and Seiki Tajima
11 Imbalances of Inhibitory and Excitatory Systems in Autism
Spectrum Disorders �� 209
Reed C. Carroll
12 Shared Developmental Neuropathological Traits Between
Autism and Environmental Lead Exposures: Insights
into Convergent Sulfur-Dependent Neurobiological Mechanisms�� 227
Lorenz S. Neuwirth, Michelle A. Vasquez, Mohammad Mian,
Angelina M. Gagliardi, Bright U. Emenike, and Morri E. Markowitz
13
Epidemiological Surveys of ASD: Current Findings and New
Directions�� 251
Eric Fombonne
14
Metabolic Approaches to the Treatment of Autism Spectrum
Disorders�� 291
Neluwa-Liyanage R. Indika, Susan C. Owens, Udara D. Senarathne,
Andreas M. Grabrucker, Nelson S. K. Lam, Kerri Louati,
Greer McGuinness, and Richard E. Frye
15 Autism and Neurodiversity �� 313
T. A. Meridian McDonald
16 Principal Findings of Auditory Evoked Potentials in Autism
Spectrum Disorder�� 333
Carla Gentile Matas, Fernanda Cristina Leite Magliaro Aburaya,
Mariana Keiko Kamita, and Rebeca Yuko Couto Kawai de Souza
17 Developmental Origins of the Structural Defects Implicated
in ASD: Insights from iPSC and Post-Mortem Studies�� 349
Rana Fetit, Thomas Pratt, and David Price
18 Genes and their Involvement in the Pathogenesis of Autism
Spectrum Disorder: Insights from Earlier Genetic Studies�� 375
Rishabh Chaudhary and Emma Steinson
19
Electrophysiology of Semantic Processing in ASD�� 417
Mirella Manfredi and Emily Coderre
20 Gestational Exposure to Di-n-Butyl Phthalate Induces
Autism-Like Behavior Through Inhibition
of Neuro-Steroidogenesis�� 433
Françoise Sidime, Meriem Bendaoud, Maisara Abdelgawad,
and Abdeslem El Idrissi
Index�� 449
Chapter 1
Dysfunctional Circuit Mechanisms
of Sensory Processing in FXS and ASD:
Insights from Mouse Models
Anubhuti Goel
The art of being wise is knowing what to overlook

– William James
1.1 Sensory Processing and Decision Making
Deciding if one should smile or be sober and if the constant noise in the background
is not relevant to the current conversation is imperative for any social interaction or
cognition. There is no doubt that decisions and choices are heavily influenced by
sensory input, and thus arises the question of how do the building blocks in the brain
decide which sensory input is relevant to the current context and which one to over-
look (not be distracted by). Imagine a scene at a restaurant where a group of friends
are enjoying a meal or a late Saturday morning at the park, with kids running around
and playing. In both scenarios, during a social interaction at dinner or at play, the
decision to show joy or sympathy is dependent on whether the person we are inter-
acting with is smiling or sad–thus processing the visual input and other sensory
information is key to deciding the appropriate social response and any subsequent
actions. Therefore, discriminating between sensory stimuli across modalities is an
important prerequisite to most behaviors. Understanding how sensory stimuli shape
decisions and judgments is particularly critical in the context of Autism Spectrum
Disorders (ASDs) and Fragile X Syndrome (FXS), where sensory issues such as
hypersensitivity to sounds, touch and sights are the most common and pervasive
symptom. Sensory atypicalities in ASD and FXS range from sensory seeking (tak-
ing pleasure from activities such as fidgeting or repeating noises, sensory distortions
in the perception of physical objects, sensory tune-outs or blanking of sound or
vision, overload of senses, difficulties in processing stimulation of more than one of
A. Goel (*)
University of California, Riverside, Riverside, CA, USA
e-mail: anubhuti.goel@ucr.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

A. El Idrissi, D. McCloskey (eds.), Neurobiology of Autism Spectrum Disorders,
https://doi.org/10.1007/978-3-031-42383-3_1
2 A. Goel
the senses at any given time, difficulty in recognizing the channel through which the
stimulation is received and suppressing targets in the visually attended area. Further,
atypical sensory experience in individuals with ASD spans across sensory modali-
ties including taste, touch, audition, smell and vision (Robertson & Baron-Cohen,
2017). While disorders associated with ASD are typically described as difficulties
in establishing eye contact and social interactions, repetitive behaviors and an atypi-
cal reduction in broader interests, an emerging view that is gaining support is that
these cognitive impairments are likely due to atypical processing and discriminating
of sensory stimuli. For example, if an individual with ASD or FXS perceives normal
stimuli as overwhelming, or is unable to tune out irrelevant stimuli then, he/she
could limit social interactions (avoiding eye contact or hugging), try to control sen-
sory inputs through rituals and experience delays in learning and adapting to
changes in the environment. Therefore, the consequence of altered sensory process-
ing is debilitating, resulting in impairment in sensory discrimination and an inabil-
ity to ignore irrelevant sensory stimuli such as innocuous sounds, smells, sights, or
touches. This hyperarousal to sensory stimuli leads to a commonly reported symp-
toms–hypersensitivity, tactile defensiveness and ADD, all of which eventually
impair learning. Indeed, several recent studies suggest that sensory issues and atypi-
cal sensory processing can be predictive of and contribute to abnormal anxiety and
other cognitive and social deficits (Wheeler et al., 2016; Kojovic et al., 2019;
Tavassoli et al., 2014; Robertson & Simmons, 2013; Green & Ben-Sasson, 2010).
At this time our understanding of how disruption in neuronal communication results
in the diverse symptoms of ASD and FXS is severely lacking. In this chapter I will
discuss what we have learned from using animal models of FXS and ASD to under-
stand the neural impairments contributing to atypical sensory processing and high-
light the translational potential of this approach to hopefully solving FXS and ASD.
1.2 Fragile X Syndrome
Extensive research in the field of ASD has revolved around Fragile X Syndrome
(FXS). Symptoms such as abnormal sensory sensitivity and processing is common
in humans with FXS and ASD, manifesting usually as sensory hyperarousal, hyper-
sensitivity and Attention Deficit Disorder (ADD) (Marco et al., 2011; Ethridge
et al., 2016, 2017; Miller et al., 1999; Sullivan et al., 2006). FXS, the leading known
genetic cause of atypical behaviors associated with autism spectrum disorders
(ASD) (Chudley & Hagerman, 1987; Niu et al., 2017; Yu & Berry-Kravis, 2014),
arises due to the reduced expression or loss of the Fragile X Messenger
Ribonucleoprotein 1 Protein (FMRP). FMRP is an mRNA binding protein that, in
response to neuronal activity, negatively regulates the translation of many mRNAs
that encode proteins important for neuronal development and synaptic function
(Darnell et al., 2011; Bassell & Warren, 2008). Hence, FMRP is important for syn-
apse maturation and experience-dependent rewiring of brain circuits through its
regulation of protein synthesis (Kooy et al., 2000; Ronesi & Huber, 2008).
1 Dysfunctional Circuit Mechanisms of Sensory Processing in FXS and ASD: Insights… 3
Interestingly, some of the signaling pathways regulated by FMRP are also impli-
cated in other ASDs (Parikshak et al., 2013) and alterations in neuronal and circuit
excitability, a hallmark of FXS (Contractor et al., 2015), may be a key to understand
autism more generally (Rubenstein & Merzenich, 2003). This argument suggests
that elucidating circuit-level alterations in FXS may not only accelerate the devel-
opment of therapeutics in FXS but may also be of broad importance to other types
of ASD and intellectual disability.
1.3 Mouse Models of Fragile X Syndrome and ASD
There is a significant overlap in the attentional impairments between FXS and ASD
symptoms (Hagerman & Hagerman, 2002). Further there is a growing consensus
that these attentional impairments could arise from sensory processing deficits.
However, the underlying neural causes of the sensory and attentional deficits are
unknown. To dissect the circuit mechanisms of sensory processing and how this
sensory deficit contributes to learning, attention and decision making, research has
utilized the potential of animal models of FXS and ASD. One well established
model–the Fragile X Messenger Ribonucleoprotein 1 gene (Fmr1) knockout (KO)
mouse, is popular for many reasons as discussed here. The mouse Fmr1 gene prod-
uct shares 97% homology with human FMRP including a conservation of the CGG
repeats (Ashley et al., 1993). Fmr1 KO mice show functional alterations that are
similar to humans and hypersensitivity phenotypes in mice resonate with human
symptoms (Consortium, D.-B.F.X, 1994; Kazdoba et al., 2014). There is evidence
that abnormal sensory processing in animal models of ASD, can also contribute to
abnormal anxiety and social impairments (Orefice et al., 2016). Further several
symptoms such as auditory startle, audiogenic seizure, visual deficits such as dis-
criminating between orientations and contrasts, have been reliably observed in
mouse models of FXS (Razak et al., 2021).
Several studies in humans have examined the oscillatory dynamics associated
with FXS, and found a reduction in alpha power and enhancement in theta power in
resting state EEG data (Van der Molen et al., 2012). The reduction in alpha power is
suggestive of a disruption in inhibition that impairs task irrelevant information from
being actively processed–leading to attentional deficits, hypersensitivity and dis-
tractibility. Further a disruption in oscillatory dynamics is interpreted as an impair-
ment in the Excitation-Inhibition (E-I) balance. Single-cell mRNA expression
studies have shown that many genes that are differentially expressed in human ASD
are interneuron-specific genes, including PVALB, SST and VIP (which are all
downregulated in ASD) (Polioudakis et al., 2019; Velmeshev et al., 2019)–again
suggestive of a disruption in inhibition. The huge explosion of recording and imag-
ing techniques combined with mouse genetics over the last decade as well as opto-
genetic manipulation of specific subsets of cells in mice allow examination of
dysfunctional interneurons and E-I balance in sensory processing. Importantly,
similar EEG phenotypes of sensory abnormalities such as increased magnitude and
4 A. Goel
reduced habituation of sound-evoked responses (Lovelace et al., 2016), are seen

across species in FXS (Lovelace et al., 2018). Therefore, for several reasons, Fmr1
KO mouse in particular, has emerged as a popular model system to study the molec-
ular and cellular pathogenesis of FXS. And given the overlap in sensory issues
across FXS and ASD, dissecting the dysfunctional synaptic and circuit impairments
in FXS will shed light on defects in circuit mechanisms in ASD in general.
Currently, there exists neither a cure for FXS nor any therapy that can reverse its
core pathogenic mechanisms. The development of viable and effective therapies in
FXS and ASD is hampered by a lack of understanding in: (1) circuit mechanisms of
atypical sensory processing in FXS and ASD, (2) the relationship of impairments in
synaptic and cellular physiology to atypical circuit dynamics, and (3) the relation-
ship of impaired sensory processing (at the level of synapses and circuits) to learn-
ing, social processing and other cognition impaired in FXS and ASD (Fig. 1.1).
Various research groups, highlight parallel alterations in neural responses to sensory
stimuli in FXS mice and humans (Ethridge et al., 2016; Lovelace et al., 2018; Goel
et al., 2018), thus insights from mouse models of FXS will provide the basis for
future translational studies and pave the way for more viable therapies in FXS and
potentially other ASDs (Fig. 1.1)
Rodent behavior
-
Translational Goal
- -
Presynaptic Network mechanisms
Human behavior
Postsynaptic
Synaptic mechanisms
Fig. 1.1 Linking sensory discrimination to complex behavior. Several components are critical to
generating complex behavior: genetic, synaptic and network. Studies in mouse models of FXS and
ASD will allow probing/understanding of different components so that we can delineate how
behavior emerges from neuronal communication. The ultimate goal of FXS research is to use
insights from mouse models to understand mechanisms linked to human behavior and find solu-
tions for neurodevelopmental disorders
1.4 Sensory Processing Deficits in the Context

of Impaired Inhibition
Sensory cortex undergoes a maturation and refinement during development which

allows emergence of a functional architecture between the different cell types and
emergence of sensory maps. These cortical dynamics are then integral to sensory
discrimination, perceptual learning and behavior throughout adulthood (Froemke,
2015). The emerging cortical dynamics have to be orchestrated across multiple syn-
apses in order to maintain the general neural coding mechanisms and strategies,
including a balance between excitation and inhibition. Maturation of inhibition is
synergistic with excitation and has several roles to play – (1) regulating the genera-
tion of spikes at cells, (2) shaping responses of excitatory cells to specific stimulus
features, (3) regulating the brain state and, importantly, (4) defining the closure of
the critical period (Isaacson & Scanziani, 2011; Fishell & Rudy, 2011). Critical
periods during early postnatal development allow plasticity and refinement of corti-
cal circuits. Several studies across sensory modalities have shown that closure of
critical periods during development adults reduces the available plasticity mecha-
nisms, thus limiting the modification of circuits and synapses in adult cortex. The
closure poses a problem for neurodevelopmental disorders, where enhancing plas-
ticity in adulthood can be beneficial and improve the efficacy of therapeutic strate-
gies by overcoming early abnormal development and closure of critical period.
Hence given the importance of inhibition in shaping cortical dynamics during
development and through adulthood, any disruptions in inhibition in neurodevelop-
mental disorders such as ASD and FXS is a problem. This realization led to the idea
that a defect in inhibition is a central problem in ASD and FXS. Further there is
mounting evidence from clinicians, psychiatrists and scientists that individuals with
ASD and FXS experience atypical sensory sensitivity across different sensory
modalities. There is a growing consensus that sensory issues and atypical sensory
processing can be predictive of and contribute to abnormal anxiety, learning and
other cognitive and social deficits (Wheeler et al., 2016; Kojovic et al., 2019;
Tavassoli et al., 2014; Robertson & Simmons, 2013; Green & Ben-Sasson, 2010).
And as I explained at the start of this chapter the influence of sensory processing is
crucial prerequisite to behavior and cognition. These different ideas have resulted in
the redirection of ASD and FXS research on understanding the role of inhibition and
excitation-inhibition balance in sensory processing and resulting behavior. While
excitation-inhibition balance is a broad overarching concept that defines brain func-
tion and behavior to a large extent, how does the complex interplay between excit-
atory and inhibitory neurons generate a fine orchestration? How is this orchestration
disrupted in ASD and FXS to result in atypical learning, social interactions and
cognition?
Further adding to the complexity of these questions is the fact that the inhibitory
system is highly complex. The complexity arises from the large variety of interneu-
ron subtypes (Petilla Interneuron Nomenclature, G, 2008), cortical inhibitory cells
can synapse onto different compartments of excitatory cells, such as soma, axonal
6 A. Goel
hillock and dendrites, and interneurons innervate different layers of the cortex.
Further, interneurons can control the output of excitatory cells as well as inhibitory
cells. In addition to the dynamic role of inhibition, studies have shown that anatomi-
cal constraints, spatially restrict the inhibitory influence on cortical networks
(Froemke, 2015). This was first observed in the hippocampus where a conserved
ratio of excitatory and inhibitory synapses was found on the dendrite of the hippo-
campal neurons (Liu, 2004). More recently, a study using visual cortical slices
showed that ratio of evoked inhibition scaled proportionally to the magnitude of
excitation (Xue et al., 2014). This underscores the idea that influence of inhibition
on circuit function and behavior is profound, therefore any disruptions in inhibition
in neurodevelopmental disorders such as ASD need to be thoroughly examined.
1.5 Inhibition in the Neurotypical Sensory Cortex
Inhibition in the sensory cortex is mediated by three populations of interneurons–

Parvalbumin (PV), Somatostatin (SST) and Vasoactive Intestinal Peptide (VIP)
neurons (Gonchar & Burkhalter, 1997) (Fig. 1.2). PV interneurons, the most prev-
alent inhibitory neuron in the sensory cortex, synapses on the soma and axonal
hillock of pyramidal cells (Gonchar & Burkhalter, 1997; Wood et al., 2017). PV
cells are not selective and exhibit very broad orientation tuning by simply respond-
ing to all orientations, since they receive local input from a wide range of orienta-
tion tuned pyramidal cells (Zariwala et al., 2012; Hofer et al., 2011; Runyan &
Sur, 2013). Furthermore, selective stimulation of PV cells in V1 with channelrho-
dopsin-2 leads to improved feature selectivity and visual discrimination (Lee
et al., 2012). SST neurons contact the distal dendrite of excitatory cells and exhibit
broader spikes and lower firing rates, compared to PV cells. Further, SST cells
exhibit a broad range of receptive field properties, orientation and direction tuning
(Ma et al., 2010). VIP neurons inhibit PV and SST interneurons, thereby reducing
tonic inhibition of target pyramidal neurons. Through this disinhibitory circuit,
VIP cells can increase the gain of pyramidal neurons during reinforcement learn-
ing (Letzkus et al., 2011; Pi et al., 2013; Jiang et al., 2013) by reducing tonic
inhibition of target pyramidal neurons. Recent work shows that a small subset of
VIP cells exhibit more canonical inhibitory properties by directly inhibiting the
pyramidal neurons (Guet-McCreight et al., 2020; Harris et al., 2018; Bezaire &
Soltesz, 2013). Each interneuron type has a specific role in shaping selectivity and
fine-tuning excitatory output. VIP interneurons in the sensory cortex are also
under the influence of cholinergic input from subcortical areas, such as the nucleus
basalis. Subcortical neuromodulation is a robust mechanism that desynchronizes
the pyramidal cell activity in the visual cortex, enhances the magnitude and reli-
ability of visually evoked responses, thus aiding detection of sensory stimuli and
making learned associations (Bennett et al., 2013; Fu et al., 2014; Pinto et al.,
2013; Carcea & Froemke, 2013; Lee et al., 2014; Goard & Dan, 2009; Pafundo
Fig. 1.2 Potential dysfunctional sensory cortical mechanisms associated with FXS and
ASD. Perceptual learning and selectivity to sensory stimuli in layer 2/3 sensory cortex can be
modulated by local interneuron dynamics as well as by cholinergic input from nucleus basalis
(NB) and top-down input from anterior cingulate cortex (ACC). (A1) Neurotypical circuits under
basal/unaroused conditions have a low cholinergic tone. (A2) During perceptual learning long
range input to sensory cortex increases thus modulating VIP cells and the dynamics involving other
cell types. This allows selective modulation of PYR cells. (B1) Hypothesis: Circuits in FXS have
an elevated basal cholinergic tone that disrupts basal VIP activity and local interneuron dynamics,
thus reducing the dynamic range and selectivity of PYR cells. (B2) Hypothesis: In FXS, disruption
in long range inputs to sensory cortex, for example elevated cholinergic tone, renders the cells
unable to respond to any further enhancement in cholinergic tone. Further diminished input from
ACC in FXS, reduces selectivity and increases the susceptibility to distractors. These hypotheses
remain to be tested. VIP: vasoactive intestinal polypeptide, PV: parvalbumin, SST: somatostatin,
PYR: pyramidal
et al., 2016). Therefore, in summary VIP neurons can dynamically regulate sen-
sory responses and plasticity as a function of the behavioral brain state and arousal
of the animal (Fig. 1.2). Hence, while the field realizes that the dysfunctional
inhibition is the underlying cause of many symptoms associated with FXS
8 A. Goel
and ASD, investigating how inhibitory neurons (and by association excitatory

neurons) communicate with each other will be instrumental in understand-
ing dysfunctional sensory sensitivity, arousal, learning and decision making
in FXS and ASD (Fig. 1.2). This is underscored by the quote from Belmonte
et al., 2004, “the heterogeneity of neuropatho-logical and genetic observations in
autism suggests that autism’s essential characteristic may not be any specific cel-
lular pathology, but rather a perturbation of the network properties that emerge
when neurons interact” (Belmonte et al., 2004)
In the remainder of this chapter I will describe the current research landscape in
FXS and ASD in the context of sensory deficits and the associated neural impair-
ments across three modalities–Visual, Auditory and Somatosensory.
1.6 Sensory Deficits in the Visual Domain
1.6.1 Humans
Over the decades several visual sensory deficits have been associated with FXS
and ASD. One technique that has allowed studying the sensory-cognitive defects
is event-related potential (ERP). This technique allows examining changes in
neural population activity in response to specific sensory and cognitive pro-
cesses. ERPs are typically detected using electroencephalograms (EEG) and
magnetoencephalograms (MEG). EEG data consist of N1 and P2 components
and are reflective of sensory processing. Studies in individuals with FXS have
shown an enhancement in N1 component of visual stimuli (Van der Molen & Van
der Molen, 2013), indicative of hyperexcitability and a disruption in E-I balance.
Visual-motor dysfunction in ASD include disruption in drawing, constructing
abstract designs (Crowe & Hay, 1990; Freund & Reiss, 1991). Other studies of
children with autism showed a deficit in the ability to detect coherent motion
(Milne et al., 2002) and contrast detection (Farzin et al., 2008). Children with
ASD also showed reduced “spatial suppression”, which is an enhancement in
perceiving motion of high contrast stimuli, again indicative of disruption in
excitatory-inhibitory balance (Foss-Feig et al., 2013). Another common deficit is
the stronger image center bias irrespective of object distribution. Here individu-
als with ASD were shown images of different scenes, for example a desk or a
bedroom. Using gaze tracking researchers found that, compared to neurotypical
controls, individuals with ASD fixated on the center of the image, irrespective of
the components in the visual scene (Wang et al., 2015). Therefore, a combination
of ERP and gaze tracking methods have revealed several sensory processing
issues in FXS and ASD that are manifested in a range of different symptoms. The
neural mechanisms, however, remain largely unknown and this has necessitated
research using animal models.
1.6.2 Mice
Some of the early studies in Fmr1 KO mice examining the neural underpinnings of
lack of Fmr1 were focused on examining a disruption in mGluR5 signaling. mGluR5
signaling is downregulated during development in the neurotypical cortex. However
Fmr1 KO mice showed enhanced mGluR5 signaling (Dudek & Bear, 1989). Some
of the early studies linking lack of Fmr1 to behavior, found that FMRP and mGluR5
was required for ocular dominance plasticity, a classic experience dependent plas-
ticity in the visual system, which allows development of binocular vision. In normal
mice, the responsiveness of neurons in the binocular zone of primary visual cortex
(V1b) is dominated by input from the contralateral eye. However, depriving the
contralateral eye of input for 3–4 d by monocular deprivation (MD) during the criti-
cal period for the visual domain (∼postnatal day (P)19–P32 in the mouse), causes a
shift in V1b responsiveness toward the non-deprived ipsilateral eye (Gordon &
Stryker, 1996). Studies showed that FMRP constrains OD plasticity and an absence
of FMRP in Fmr1 KO mice showed aberrant OD plasticity (Dolen & Bear, 2008;
Dolen et al., 2007). As the visual system matures, refines and develops through
visual experience, an important milestone is keeping track of familiar features that
allow recognition of familiar objects. An inability to discriminate between familiar
and novel objects can contribute to disruption in higher order social cognitions, as
is often observed in FXS humans and in Fmr1 KO mice. One study found that visual
familiarity is encoded in visually evoked low frequency oscillations (Kissinger
et al., 2018). In Fmr1 KO mice, these oscillations were reduced in power and shorter
in duration, and mediated by a reduced enhancement in synaptic strength from layer
5 pyramidal cells onto layer 4 fast spiking cells (inhibitory cells), indicating a dis-
ruption in neural mechanisms that encode for familiarity (Kissinger et al., 2020).
Studies in humans with FXS and Fmr1 KO mice showed that maturations and
refinement of dendritic spines required FMRP and lack of FMRP in visual cortex of
Fmr1 KO resulted in immature spines. Dolen et al. 2007 found that Fmr1 KO exhib-
ited a reduction in spine density and this could be rescued by a 50% reduction in
mGluR5 expression (Dolen et al., 2007). Therefore, these studies set the stage for
the role of FMRP and atypical enhancement of mGluR5 as the neural contributors
to visual processing and impairments. However, how these molecules cause dys-
functional circuits and ultimately atypical behavior is unknown.
Since inhibition has a powerful influence on maturation of cortical circuits, an
investigation of the role of inhibition in FXS and ASD showed a ~50% reduction in
the mRNA of α1, α3, α4, β1, β2, γ1, and γ2 GABA receptor subunits and a decrease
in α1, β2, and δ GABA receptor subunits (Adusei et al., 2010; El Idrissi et al., 2005;
D’Hulst et al., 2006). Further several lines of converging evidence from human and
animal studies support a role for PV interneuron hypofunction in the pathogenesis
of autism: (1) reduced density of PV interneurons and lower expression levels of the
protein (2) the density of PNNs around interneurons is decreased. In the neurotypi-
cal cortex PV cells exhibit very broad orientation tuning (Zariwala et al., 2012;
10 A. Goel
Hofer et al., 2011; Runyan & Sur, 2013), contribute to the selectivity of pyramidal
cells (Lee et al., 2012) (although SST cells have also been show to influence pyra-
midal cell tuning) and cortical gain of V1 (Atallah et al., 2012). Therefore given the
mounting evidence that sensory processing is heavily influenced by PV cells, an
emerging idea is that a disruption in PV function, leads to atypical communication,
“handshake” between PV cells and pyramidal cells contributing to many symptoms
in FXS and potentially ASD (Contractor et al., 2021). More generally several stud-
ies have shown that the influence of lack of Fmr1 on inhibitory and excitatory func-
tion is varied and complex. While studies have shown a disruption in PV cells, an
investigation of the contribution of this disruption to FXS symptoms is more recent
(Contractor et al., 2015; Cea-Del Rio & Huntsman, 2014). In the visual cortex
hypoactivity of parvalbumin (PV) expressing cortical interneurons leads to impaired
perceptual learning in Fmr1 KO mice and restoration of PV function using a
DREADD approach rescues learning (Goel et al., 2018). Hypoactivity of PV cells
was accompanied by a reduction in percentage of orientation tuned cells, broader
tuning of existing pyramidal cells and correlated with impaired learning.
Chemogenetic rescue of PV function also had ameliorative effects on orientation
selectivity and tuning (Goel et al., 2018).
PV cells interact with different inhibitory and excitatory cells in a dynamic fash-
ion and thus the influence of PV cells on the circuit and behavior is complex
(Fig. 1.2). PV cells are shown to be modulated by other interneurons such as VIP
cells and SST cells, as well pyramidal cells, which are excitatory. While this has not
been tested, the prediction is that atypical sensory processing could result from a
disruption at any, or a combination of the loci in the complex circuit (Fig. 1.2).
Further, recent studies have shown that PV and pyramidal cells do not develop in
isolation, rather the development and maturation of both cell types is a synergistic
process requiring both their functional contribution during early postnatal develop-
ment (Wong et al., 2018)– contributing to the “handshake”. During neurotypical
neocortical development in mice, pruning of interneuron population occurs where
excess neurons are eliminated by pyramidal neuron activity (Wong & Marin, 2019;
Southwell et al., 2012). In juvenile mice, during the first postnatal week, both inhib-
itory and pyramidal neurons collaborate in synchronous bursts of activity (Golshani
et al., 2009). Collectively studies in mice suggest that development of cortical net-
work activity and establishment of an E-I balance is dependent on the regulation of
interneurons in an activity dependent manner (Wong et al., 2018; Wong & Marin,
2019; Dana et al., 2019). Therefore, reduced PV cell density in ASD could be caused
by disruptions in early cortical network activity, or in their ability to establish func-
tional connections with pyramidal neurons. Further any disruption in the “hand-
shake” can influence development and maturations of the circuits in the sensory
cortex, thus affecting sensory processing.
As shown in Fig. 1.2, PV cell function is heavily influenced by other interneu-
rons in the circuit. In particular, the influence of VIP interneurons on PV cells, SST
cells and sensory processing has received a lot of recent attention. There are many
reasons for this.
VIP cells are modulated by local intracortical circuits as well as two well
studied long-range afferents–top-down inputs from anterior cingulate cortex
(ACC) and subcortical cholinergic inputs from nucleus basalis (NB). These long
range afferents have been shown to modulate sensory processing in primary
visual cortex (V1) of wild type (WT) mice. The following discussion highlights
the importance of long range and local inputs to VIP cells in the context of FXS
and ASD.
1. Influence of long range afferents on VIP cells. Top-down modulation from fron-
tal cortical areas is important in perceptual learning by allowing visual cortical
neurons to maximize their responses to behaviorally relevant stimuli and discard
input from competing distractors (Desimone & Duncan, 1995; Gilbert & Li,
2013; Li et al., 2004). One specific frontal cortical area–anterior cingulate cortex
has been implicated in tasks involving attention, detecting change in stimuli,
error detection and contribute to emergence of stimulus selective responses
(Posner & Petersen, 1990; Garavan et al., 2002; Menon et al., 2001; Fiser et al.,
2016). Recent studies in mice have shown that stimulation of ACC in mice,
selectively modulates visual processing (Zhang et al., 2014) and viral tracing
studies identified projection neurons in ACC that densely innervate V1 (Zhang
et al., 2016). Studies in humans with FXS and ASD have shown disruptions in
ACC activity (Minshew & Keller, 2010), reduced AAC activity during attentive
tasks (Chan et al., 2011) and reduced glutamate metabolism in ACC (Tebartz van
Elst et al., 2014). Therefore, ACC improves selectivity to behaviorally relevant
stimuli and FXS and ASD is associated with hypersensitivity to sensory stimuli
and impairments in ACC function. However, the contribution of ACC afferent on
sensory processing in V1 or its influence on VIP cells in FXS remains to be
investigated. Subcortical neuromodulation to V1 enhances the magnitude and
reliability of visually evoked responses, thus aiding detection of sensory stimuli
and making learned associations (Bennett et al., 2013; Fu et al., 2014; Pinto
et al., 2013; Jimenez-Martin et al., 2021; Hasselmo & Giocomo, 2006).
Specifically, basal forebrain stimulation enhanced magnitude and reliability of
orientation specific responses in V1 (Goard & Dan, 2009; Pafundo et al., 2016)
and optogenetic activation of cholinergic input to V1 improved visual discrimi-
nation learning by reducing the variation over trials (Pinto et al., 2013). Several
studies in Fmr1 KO mice show overactive cholinergic signaling (Volk et al.,
2007; Veeraragavan et al., 2012; D’Antuono et al., 2003) including deficits in
learning (Volk et al., 2007) which can contribute to anxiety, repetitive behavior
and hypersensitivity.
2. Local effects of VIP cell dynamics: VIP cells mediate a disinhibitory circuit,
which has emerged as an intracortical mechanism for providing cholinergic
modulation to neural circuits in different parts of the brain. Sensory responses by
cortical neurons are modulated by different behavioral states, and cholinergic
modulation has been shown to improve discrimination by reducing trial to trial
variability (Goard & Dan, 2009; Pafundo et al., 2016; Metherate et al., 1992).
12 A. Goel
Visual and auditory responses are accompanied by robust, phasic activity in VIP
neurons (Pi et al., 2013; Reimer et al., 2014; Fu et al., 2014), which are strongly
driven by basal forebrain stimulation (Pinto et al., 2013). Thus, VIP cells can
relay cholinergic inputs to excitatory neurons in order to dynamically regulate
their sensory responses as a function of the behavioral brain state of the animal
(Fig. 1.2). This line of reasoning is supported by the fact that VIP cells mediate
the enhancement of visually-evoked responses by locomotion, i.e., a heightened
state of arousal (Fu et al., 2014). Ultimately, VIP neurons inhibit PV and SST
interneurons, thereby reducing tonic inhibition of target pyramidal neurons.
Through this disinhibitory circuit, VIP cells can increase the gain of pyramidal
neurons during reinforcement learning (Letzkus et al., 2011; Pi et al., 2013).
Also, in mice performing an auditory detection task that required sustained
attention, cholinergic neurons responded most strongly to the unexpectedness of
the reinforcement (Hangya et al., 2015). Collectively these studies underscore
the influence of VIP cells in sensory processing and suggest that disruption of
VIP function can have a lasting impact on cortical dynamics and perceptual
learning.
Recognizing the importance of VIP cells, recent work has examined the role of
developmental disruption of VIP function. One study used a genetic approach to
produce a disruption of VIP function during development (Batista-Brito et al.,
2017). The genetic manipulation involved a disruption in ErbB4-Nrg1signalling,
which is an important pathway in interneuron development. They found that dis-
rupting ErbB4-Nrg1signalling did not change overall density of VIP, PV or SST
cells, however dramatic impairments were reported in the cortical dynamics– fur-
ther highlighting the importance of examining circuit deficits associated with
interneuron dysfunction. Extracellular recordings from awake mice showed an
elevation in firing, reduced bursting and decreased firing rate variability in regular
spiking cells (putative excitatory cells). Further, there was a drastic reduction in
phase locking of regular spiking (excitatory) cells to low frequency and gamma
oscillations. Optimal sensory processing and learning requires temporal syn-
chrony and organization is cortical circuits and this feature of cortical dynamics
was disrupted by developmental disruption of VIP function. VIP cells can relay
cholinergic inputs to excitatory neurons in order to dynamically regulate their
sensory responses as a function of the behavioral brain state of the animal.
Therefore, it was not surprising that atypical VIP development resulted in an
absence of cortical state transitions, reduced orientation selectivity of RS neurons
and deficits in performing a visual discrimination task (Batista-Brito et al., 2017).
Investigation of VIP function deficits in a mouse model of Rett Syndrome also
showed impaired cortical dynamics, state modulation and deficits in performing
social tasks (Mossner et al., 2020)
Future research needs to be targeted towards improving our understanding of
dysfunctional long-range influence on VIP cells and whether the link between VIP,
PV, SST neurons and arousal/reinforcement is disrupted in FXS.
1.7 Sensory Deficits in the Auditory Domain
Atypical exaggerated responses to sounds and an inability to habituate to irrelevant

sounds is a hallmark of the auditory hypersensitivity phenotype, often reported in
FXS. It is measured using a pre-pulse inhibition (PPI) assay (Frankland et al., 2004).
In this assay subjects are presented with a less intense auditory stimuli (pre-pulse
stimulus) followed by a louder startle stimulus. The pre-pulse stimulus reduces the
response to the following startle stimulus and is measured as PPI. Reduced PPI has
been observed in individuals with FXS but not in ASD. PPI is a standard and reli-
able outcome measure that is often used to assay the efficacy of treatments, both in
mice and humans. Further the magnitude of PPI response is correlated with deficits
in attention, autism and adaptive behaviors (Frankland et al., 2004). Fmr1 KO mice
show a similar robust enhancement in PPI109. Auditory hypersensitivity can be asso-
ciated with an atypical enhancement auditory cortex function. Indeed some of the
early reports showed an enhancement in responses to sounds and broader frequency
tuning of adult cortical neurons (Rotschafer & Razak, 2013). This disruption of
cortical function is conserved across modalities– visual cortical neurons (Goel
et al., 2018) and neurons in the somatosensory cortex (Arnett et al., 2014) also
exhibit broader tuning. Collectively, studies across modalities show that neurons in
the sensory cortex of Fmr1 KO mice have reduced stimulus selectivity and hence,
sensory stimuli recruit a larger proportion of cortical neurons and a potential disrup-
tion in inhibition results in a sustained enhancement of cortical activity.
Several studies in humans using EEG have shown an enhancement in the magni-
tude of N1 component (Van der Molen et al., 2012; Van der Molen & Van der Molen,
2013; Rojas et al., 2001; Castren et al., 2003) and a reduction in N1 habituation
(Castren et al., 2003). Further, a study using MEG found an enlargement and reduced
latency of the N100m112. Pioneering work from the Razak lab, using EEG recordings
in mice, has shown parallel EEG phenotypes in Fmr1 KO mice and individuals with
FXS (Lovelace et al., 2016, 2018). Atypical EEG phenotypes include enhanced EEG
gamma band power, reduced cross frequency coupling, reduced sound-evoked syn-
chrony of neural response at gamma band frequencies and audiogenic seizures
(Lovelace et al., 2018, 2020) and a lack of modulation in the auditory startle response,
irrespective to stimulus intensity. This lack of modulation in the behavioral response
is another feature that is observed consistently in Fmr1 KO mice across modalities
(He et al., 2017; Nielsen et al., 2002). Reduced stimulus selectivity, enhanced non
phase locked EEG responses are indicative of a reduced signal to noise ratio, which
can lead to a disruption in sensory discrimination. Cortical activity in the gamma
range is associated with a range of sensory and cognitive processes, therefore disrup-
tion in gamma activity can contribute to many of the symptoms associated with FXS
and ASD. Indeed, enhanced PPI and gamma activity is also reported in Shank3B null
mutant mouse, a mouse model of ASD (Dhamne et al., 2017), that also causes the rare
neurodevelopmental disorder Phelan McDermid Syndrome (PMS)
Aberrant gamma function can also be explained by deficits in PV function. For
example, a single PV neuron synapses onto multiple neighboring pyramidal cells
14 A. Goel
(Runyan & Sur, 2013) providing synchronous inhibition that can coordinate genera-
tion of gamma activity (Cardin et al., 2009; Sohal et al., 2009). Although somatosta-
tin cells in the visual cortex have also shown to be required for context dependent
gamma rhythm generation (Veit et al., 2017). However, the contribution of any dis-
ruptions in SOM cells to sensory processing or hypersensitivity impairments in
FXS remains to be investigated.
Specialized extracellular matrix structures called the perineuronal nets (PNNs)
also influence PV function and observed reduction in PNN ensheathed PV cells in
Fmr1 KO have been associated with disruption in fear conditioning (Reinhard
et al., 2019).
1.8 Sensory Deficits in Somatosensory Domain
The sensory deficits observed in Fmr1 KO mice prompted researchers to identify a

reduction in the number of PV cells in somatosensory cortical tissue early on (Selby
et al., 2007). Further somatosensory cortical neurons of Fmr1 KO, also showed a
decrease in fast spiking inhibitory neuron activity and an increase in excitatory
function (Gibson et al., 2008; Hays et al., 2011; Paluszkiewicz et al., 2011), result-
ing in a disruption in network activity, measured as long UP states (Gibson et al.,
2008; Hays et al., 2011) and decrease in synchrony of gamma waves (Gibson et al.,
2008). Long UP states were specific to a deletion of Fmr1 in glutamatergic cells and
not GABAergic (inhibitory) cells, highlighting the complexity of the interaction
between excitatory and inhibitory cells. Prolonged UP states were attributed to the
hyperfunction of mGluR5 receptors on excitatory neurons (Hays et al., 2011). Up
states are a well-studied signature of cortical network dynamics. It is a network
wide phenomenon where a large population of neurons mutually contribute to a
sustained depolarization. Up states influence memory consolidation, homeostatic
plasticity as well as some interpretations suggest that Up states contribute to the
decorrelation of activity during arousal. Therefore, a disruption in Up states can
have significant impact on sensory processing and perceptual learning. Indeed, a
lack of decorrelation in somatosensory cortical network activity has been reported
in Fmr1 KO mice (Golshani et al., 2009; Goncalves et al., 2013) and this decorrela-
tion is attributed to deficits in selective processing of stimuli and learning. A study
using an ex vivo model system (organotypic slice cultures) showed a delay in emer-
gence of Up states. This resulted in enhanced variability in the spatiotemporal struc-
ture of Up states. The variability prevented circuits from learning a temporal pattern
(Motanis & Buonomano, 2020).
Reduced feedforward inhibition, mediated by PV cells, has also been observed
in several other mouse models of ASD such as Cntnap2−/−, 16p11.2del/+, Tsc2+/−)
(Antoine et al., 2019). Disruption in network synchrony has also been observed in
Cntnap2−/− mice (Penagarikano et al., 2011). Ca2+ imaging studies during develop-
ment have shown that in juvenile mice, somatosensory cortical neurons of Fmr1 KO
mice, show increased synchrony of cortical activity and an elevation in firing
probability during Up states (Goncalves et al., 2013). Further young and adult Fmr1
KO mice exhibited tactile defensiveness, a form of sensory hypersensitivity as mea-
sured by enhanced motor responses to innocuous whisker stimulation (He et al.,
2017). Ca2+ imaging revealed that the hypersensitivity to whisker stimulation was
accompanied by fewer time locked or stimulus selective layer 2/3 neurons in the
somatosensory cortex as well as a reduced neuronal adaptation to the innocuous
stimuli (He et al., 2017). Impaired network adaption correlated with a reduction in
time locked cells. These studies reveal a reduced range of selectivity available in
circuits of Fmr1 KO mice, reducing the flexibility and potentially the number of
computations that can be performed.
1.9 Conclusion
Choices are the hinges of destiny – Pythagoras.

Dissecting how the brain interrogates the environment and chooses/discriminates between stimuli
of different modalities will provide an important piece to the puzzle of FXS and ASD. Research
using mouse models of FXS and ASD have identified several cellular, synaptic and
circuit level defects in the associated dysfunctional circuits (Fig. 1.3). In addition,
Fig. 1.3 Summary schematic shows the synaptic and network anomalies identified in mouse mod-
els of FXS and ASD, across modalities. These deficits contribute to atypical sensory issues and
cognition
16 A. Goel
mouse models have provided a valuable characterization of sensory, learning and

behavioral defects that resonate with human symptoms. An immediate future need
in the field of FXS research is designing parallel behavior paradigms in mice and
humans, that capture sensory issues, and elucidating associated circuit dysfunction
in mice to provide a translation- and clinically-relevant read out with objectively
measurable biomarkers.
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temper. I was proud and sullen, and—ungrateful.”
“Not always that.”
“I think I hated almost everybody. I did not want to be governed or
counseled. And Stephen was so—rigid and prompt. He treated me
like a little boy—”
“Oh, hush!” I interrupted.
“Some of it is true. He admits it. And when that awful affair
happened I expected he would disown me. He is so proud, then he
never did anything bad in all his life. So I felt that I had no mercy to
expect from him.”
“But you were mistaken,” I said eagerly.
“I couldn’t have gone there and in that way but for you. Perhaps he
has told you—” and his eyes questioned mine.
“No,” I answered, glad that we had not discussed it.
“I went to him. I believe it was the first manly step of my life. But,
oh, I felt so forlorn and miserable—I can’t tell you! If he had been
cold and cross I believe I should have gone and thrown myself in the
river.”
“He was not.”
“Oh, Rose, it was like the story of the prodigal son. ‘Fell upon his
neck and kissed him.’ I remember his kissing me the day father was
buried, and I do not believe any one ever did since till then. It melted
all my soul. Somehow I think he is wonderfully changed. His
goodness is so tender.”
“And you love him?”
“Love isn’t any word. I absolutely adore him! I did not think it was
in me, or in him. And all through the weeks that followed, for I was
very ill and miserable, he was so good. I never talked to any one
before, except you, somehow I could not. But he found his way to my
heart and said he would help me, that we would both try together, for
he had many faults to correct, that God had given us the tie of
brotherhood for a high and holy purpose, that we were to help and
strengthen each other; as if, Rose—as if I could do anything for him!”
“Yes, you can,” I replied. “You can keep him tender and cordial and
brotherly.”
“So he said. We did not come to this all at once, and Mrs.
Whitcomb’s cheerfulness helped. I had to try hard to be patient. I
was so used to flying out at everything. You see, at uncle’s they all
knew that I had a bad temper, they expected me to explode or sulk
on the slightest provocation, and only laughed or tormented me. If I
had been taught to control myself, it would never have been so
dreadful.”
“It is good to have the lesson learned now.”
“I never can forget it, never! I am not an angel yet, Rose, cherubim
or seraphim, I suppose Miss Fanny would say;” and he smiled oddly,
“but I am trying. I do not disdain the helps as I used to. I do not feel
that patience and self-control are exclusively girlish virtues.”
“No,” I returned, “we girls will not rob you of them.”
“You are generous. But then you always were. I am beginning to
learn that the grand corner-stones for the human soul are truth and
love, the truth that leads us to be fair and just to others, and the love
to our neighbor.”
“Here we are,” I said. “Do you want to come in?”
He followed me and we did our errand.
“I could not understand last summer why you loved to do these
things;” he began when we were homeward-bound.
“You considered it an evidence of a depraved taste?”
He smiled rather sadly.
“I supposed people consulted their own pleasure first. Doing any
rather distasteful deed and hunting around until you found a bright
side to it was like so much Sanscrit to me.”
“He came not to please—Himself;” I said solemnly.
“I understand a little now. Yet when He had redeemed the world
there must have been a great joy in His own mind, as well as in
heaven.”
“We cannot do anything like that,” I said. “But as He loved us, so
we are to love the brethren, the whole world.”
“To be willing to do for them. To seek not our own pleasure
altogether. It is very hard, Rose, and sometimes I get discouraged.
Then Stephen tells me of his failures. It doesn’t go on continually. It
is a little doing all the time, work and healing, and he says it will have
to be so in this world.”
“Yes,” I answered. “We cannot hinder nor change. God sets the
work before us, and though the pleasant fields are all about us, we
have no right to choose our own paths. He knows best in what ways
He wants us to walk.”
“I talked to your father yesterday. I did not think I could talk to
anybody but you and Stephen. I was sorry for all the pain and
anxiety I had caused him—and—it was almost like having a father of
one’s own. I don’t wonder that you all have such sweet pleasant
natures.”
We met Lily and Tim taking a walk, their hands full of grasses and
wild flowers, so we turned them about and all went home together.
The visit proved a very delightful one. We went to the Cascade
one day, taking a lunch with us, and on another day the Churchills
sent their family carriage over and we had a royal time, crowding it
full, and taking turns in driving.
We all noticed the great change in Louis. Not that he was perfect
or saintly. In fact I think he was more of a boy, when it came to that,
than the summer before. He still had a dangerous tendency to
quickness of temper, sometimes he would flush deeply when
annoyed, but he always spoke afterward in a low, even tone of voice,
as if he had gained the mastery within. His feelings were more
healthy-toned, he had a heartsomeness that was genuine. You never
mistrusted it as you did Stuart’s.
We ended the festivities with a croquet and tea-party on Saturday
afternoon, asking in a half dozen young people who all enjoyed
themselves amazingly. To the surprise of everybody, right in the
midst of the gayety who should drop down upon us but Stephen
Duncan.
“I was homesick to see you all,” he began, with a comically
lugubrious face.
“If you think you are going to be purely ornamental you are much
mistaken;” declared Fanny. “Here is a mallet and here is a place.”
“If you will excuse me—”
“But I will not. No running away to the study to talk with papa, or to
play with Edith. If you will come uninvited to a party you must take
the consequences.”
“Can I not soften your heart, if like the old man I should ‘sit on the
stile and continue to smile?’”
“Not any smiles. I am obdurate.”
He pretended to be much aggrieved, but in reality he was very
gay. I had never seen him so amusing and entertaining.
“I don’t see how you get acquainted with such loads of nice
people;” said Allie West. “And you always have such good times
here.”
The good times came without any trying. There are numberless
gates called Beautiful all along life, at which you give such as you
have, and find it more precious than silver or gold.
It was a lovely moonlight night, so after supper we walked part of
the way with the merry crowd. It did not seem to me that I had ever
been so happy in my life. I could not tell why but I felt as if I must
have wings somewhere that were lifting me off the ground at every
step.
We rambled around under the trees and by the way side. Louis
came back to my vicinity and we fell into a rather grave talk about
the future.
“I never thought I should want to stay here so much,” he said. “I
was glad enough to get away last summer. I cannot forgive myself
for being such a boor! Now I shall want to come again and again.”
“Well why not?” I returned.
“I am afraid you will become tired of me.”
“Try us and see. We are not easily wearied.”
“You are all so generous with yourselves.”
I smiled a little. “Why not give of your best?”
“True.” Then there was a silence. We reached the gate presently.
“Do not go in just yet;” he pleaded, so we remained in the silvery
light that was flooding the whole earth. Moonlight always stirs the
tender and thoughtful side of one’s soul.
“I am glad that to-morrow will be Sunday. I can just think how I
shall enjoy going to church and hearing your father preach.”
This from him who had despised religion and sneered at sermons.
It did startle me.
“And to have Stephen here.”
“I am rejoiced that you feel so kindly toward one another,” I replied.
“You are getting to be brothers indeed.”
“And then will come weeks and weeks of study,” he went on in a
musing tone. “I like it. Books seem to me—well, better than some
people. Only—if you could all come down in the winter. Stephen and
Mrs. Whitcomb were planning for it, but there! it was a secret and I
have betrayed it.”
“I can keep secrets;” and I smiled up into his remorseful face.
“Yes; I have proved that. Rose”—after a pause—“I have half a
mind to tell you another, to ask some—advice; at least, I would like
to know how it appears to you.”
“Will it be of any real avail?” I asked, noting the perplexed lines on
his countenance. “I am not as wise as you think. Because I just
happened to stumble into one matter without making a mess of it—”
“This is only an idea. I cannot ask Stephen. I think it would please
him and he might judge wrongfully.”
“If I can help you;” I replied encouragingly.
“It is about the future. It may never come to anything to be sure,
and perhaps I never can be good enough. Stuart will go into
business. He does not love study and he needs an active life. He
wanted Stephen to put him in a store this Autumn. But I—”
I knew then what he meant. Somehow I could not help laying my
hand on his arm with a touch of confidence.
“Whether I ever could so govern my temper and my impatient
desires;” bowing his head humbly. “But if I had some guard about
me, if I felt that I must try continually—would it be wrong to think of
it?”
“Surely not;” I returned warmly. “Nor to do it if God gives the
strength and the grace.”
“I like to think of that grand, earnest Saint Paul, with his ‘thorn in
the flesh.’ Perhaps it was some giant temper or desire. I fancy it
must have been, for you know how he persecuted the Christians
unto death. And though God would not take it away, there was the
promise of His grace being sufficient.”
“As it is, always.”
“There are some years to live before I decide positively. But if they
were spent in a worthy manner, and I mean them to be, with God’s
help.”
“Oh, you could, surely. And papa would be your best friend;” I
rejoined eagerly.
“Keep my secret—I have your promise,” he said in a hurried
manner, for a step sounded on the walk.
“It is sacred to me until you wish to take others into your
confidence.”
Stephen spoke and we turned, walking slowly up to the house.
Louis sat down on the step beside papa. I stood undecided whether
to go in or not, when Stephen took my arm and drew me around the
corner of the porch. There was a long grape arbor whose gloom was
made a pleasant twilight by the silver sifted through the openings
between the leaves, and we took a turn up and down.
“I want to tell you,” he began almost abruptly, and his voice had a
hard, strained sound, “that I heard—the last of what you said. I could
not help it. And I know your secret.”
I was a trifle annoyed, but I controlled myself.
“Oh,” I said, “then you will be tender and helpful and do all in your
power to strengthen Louis. He feels so humble. I would hardly have
thought it of him. And there are so few young men who have any
desire to take such a life upon them. With his means and his talents
he can do so much good.”
He stopped suddenly. “Rose, what are you talking about?” he
asked. “Did not Louis—”
“He confessed to me his desire—no, it was hardly that, as he is
afraid he can never be good enough for a clergyman. But you will
assist him—you do not disapprove of it?”
“Louis! Ah, I understand. It would be the delight of my heart. But I
thought—I knew he liked you so much. Oh, my little darling!”
He turned and gathered me in his arms. My heart beat and my
cheeks were in a blaze as the whole story came to me, dazing me
with its strange, sweet suddenness. I believe I cried and then I
laughed hysterically, but somehow the cool, steady voice quieted me
and made me feel the truth and earnestness of what he was saying,
so presently I grew still with a great awe.
“You will come,” he was saying. “We both need you. We want just
this steady, cheerful, loving influence. I think I have a tendency to be
impatient when people cannot see my ways, perhaps requiring a
little too much, and your sweetness will temper this. Then we can
both help him.”
Could I? How strange that any one should care for me alone. Not
for mamma, or Fanny, but to want me!
“Mr. Duncan,” I began as we were going back to the porch—“have
you forgotten that my hair is—red?”
“Well, what of that?” in a gay tone.
“I do not believe you—like it.”
“You foolish little girl, set your heart at rest. Do you remember
when I came upon you suddenly last summer? You were standing on
the porch in a tiny glint of sunshine, and looked like some of the old
pictures! Why, I believe it was your hair that I fell in love with first of
all.”
“I am glad it was, for I am not half as good as you imagine I am.”
“Children,” mamma said, standing on the porch step. “Do you
realize how late it is?”
I felt that she knew all, perhaps had known it long before, indeed.
But I was glad that the knowledge had come to me so suddenly, and
not any sooner. Even now I was half afraid of it. Her kiss and tender
clasp re-assured me.
“Mother!” Stephen Duncan said with reverent sweetness.
CHAPTER XVII.
WISHED there could be no such thing as breakfast the

next morning, but there was, and I had to go through
with it, feeling that I was no longer I, that Rosalind
Endicott was some dream-girl of the past. Stephen was
very good and did not notice me much, and Fan
appeared wonderfully pre-occupied. Mamma helped me over the
trying places, and papa just said with his tender morning kiss,—“And
this little girl, too.”
When I was all dressed for church I opened a little drawer to get
my gloves. There lay the box containing Stephen’s gift. I had never
worn it, but it seemed to me as if I ought to put it on now. He liked
me and the misunderstandings were at an end. I had accepted a
share of his burthens, his crosses, whatever they might be, so I
clasped it around my neck. It was so beautiful. I did not envy the
queen her diadem.
We walked to church together. Louis glanced back now and then. I
believe he began to suspect.
It was quite different from the Sunday when I had gone to church
with that strange sense of Fan’s new love. I felt quiet and restful, yet
it was such a great thing to have another’s heart in one’s keeping, to
take in a new life beside the old.
They both left us on Monday. Stephen was to come up soon
again. In the meanwhile, letters.
“I have one of yours to begin with,” he whispered.
It was a silent day for us. No one appeared to care about talking,
yet we were not gloomy. Indeed, I think mother, Fan and I
understood as we never had before, how much we loved one
another.
I went on wearing my cross. In the first letter there came a pearl
ring for me. Fan had a handsome diamond but she seldom wore it
except when she was going to the Churchills. I slipped mine on my
finger with a slight presentiment that I should turn the pearl inside if
any one looked at me.
Richard Fairlie and Jennie came home bright and happy as birds.
They took possession of the great house, altered a little, re-arranged
to their liking and had Mrs. Ryder in their midst. There was no grand
party, but some pleasant tea-drinkings and hosts of calls. No one
could afford to slight Mrs. Fairlie, and people began to realize what a
noble girl Jennie Ryder had always been.
I am almost ashamed to confess how much talking it took to settle
our affairs. Stephen wanted to be married in the Spring. That was
too soon, mamma and I thought. But there were so many good
reasons.
Miss Churchill heard of it presently and came over to have a
consultation with mamma.
“It will have to be sometime,” she said. “It will make a little
confusion, a break, and no end of strangeness in adapting
yourselves to the new order. But here are Nellie and Daisy right
behind.”
“I don’t want to lose all my girls in this fashion,” said mamma.
Miss Churchill smiled and then admitted that she had a plan to
propose.
They wanted Fanny. The murder was out then.
“Kenton and I have discussed the matter a good while. Winthrop
will have the farm when we are done with it—he is the only nephew.
Kenton has been sorry for some years that we did not take him when
his father died. He is very fond of country life, and surely there are
enough to toil and moil in the cities. Then, although Lucy was
improved by her summer trip, we can understand that it is not
permanent. She wears out slowly. I should like her to have a happy
year or two with Fanny, and I should like the marriage well out of the
way of any sad memories.”
“You are very thoughtful,” returned mamma.
“And it will hardly be like parting with Fanny, for you—as you can
see her every day. One thing and another has brought us so near
together. Kenton and I are growing old and the presence of these
young people will keep us from getting too queer and whimsical.”
It was settled some time in January.
“We shall have to do the best we can,” said mamma. “The
wardrobes must be simple. It is our station that they go out of, and
we never have been ashamed of our poverty.”
“What does a few clothes signify,” commented papa. “If the young
men are not satisfied we will give them a double portion of dry-goods
and keep our girls.”
Fan laughed over the idea.
So it was arranged that she and Fanny should go to New York. I
did not desire to accompany them, and I was sure they could choose
as well for me as if I hunted the whole town over. Besides, I wanted
the nice quiet time with papa, since I was the one who would have to
go away.
“Isn’t it funny!” said Fan. “I feel like the heroine of some hundred
year old novel, going up to town to buy wedding clothes, instead of a
girl of the period of puffs, paniers, chignons, Grecian bends, and all
that! Why Rose, think of it! We have never had a silk dress in all our
lives, except that once we had one ruffled with an old one of
mamma’s; and we have been very tolerably happy.”
“Yes, just as happy as one need be. All that could be crowded into
our small lives.”
“I dare say we should be absolute curiosities to some people.
Everybody now-a-days has a silk walking-suit, and some handsome
thread lace, and I don’t believe there are any poor people but just us.
But then we have had the love and comfort and enjoyment and no
time to worry about our rich neighbors. It has been a life full of
pleasantness and peace.”
That was true enough. There were many, many things beside
raiment, if one could only get at the real completeness and harmony,
the secret of soul life.
Jennie Fairlie would help us sew. With their good servant she
declared she had nothing to do. Miss Churchill sent us both an
elegant poplin suit, or at least the materials. It was a simple
wardrobe to be sure. One pretty light silk dress, one dark silk with a
walking-jacket. We made morning robes and some inexpensive
house garments. Then it would be summer so soon, and there was
nothing equal to fresh, cool white. We were not used to crying for the
moon, we had found early in life that it was quite a useless
proceeding.
Altogether we kept our secrets pretty well, and when the truth
leaked out at last, everybody was so surprised that they could only
exclaim. Aunt Letty Perkins was brave enough to come and see if it
was really so.
“Well, I am beat!” she declared. “And doing well, too! I always said
there never was anyone like Mis’ Endicott for luck. Girls often do
hang on so where there is a lot, and you’ve enough left. Fanny is the
flower of the family to be sure, but she is making a big step to get in
with the Churchills. Ain’t afraid she’ll be puffed up with pride and
vanity, are you?”
“I think I can trust her,” replied mamma with a funny smile in the
corners of her mouth.
I remember the morning as one recalls a half dream, the misty
impression between sleeping and waking. The peculiar confusion
pervading the house, the strange mislaying of handkerchiefs and
gloves, the voices that were so full of tears and gay little laughs, the
half sentences, the clasp of hands as one went in or out of a room,
the long, loving glances as if each would fain garner all the past into
one sweet remembrance. Winthrop and Stephen, one rather grave
but very tender to mamma and the little ones, the other full of life and
vivacity, the happiest of the happy.
Fan had one little say though her eyes were bright with tears.
“I hope I can be as good and sweet in my life as mamma has been
in hers. And I will not ask any higher happiness.”
We walked up the church aisle. The children stood around, back of
them Louis, Nelly and mamma, and then a host of eager parish
faces. Does any one take it all in then, the solemn questions, the still
more solemn promises?
Mr. Churchill gave us both away. Papa’s voice had a little falter in
it, and I dared not look up. “For better, for worse,” “till death do us
part,” rang clearly in heart and brain. The forever of human love,
when it is love and no base counterfeit.
A little kissing, a few tears, some tremulous whispers and sad, sad
good-byes. We whose farthest journey had been the brief sojourn at
Martha’s Vineyard, took up the great pilgrimage of a new life.
I cannot tell you anything about it, or Stephen. It was a happy

confusion of strange places and watchful care, bits of affection
shining out of the tiniest rift. Honeymoons, I suppose, are much
alike, but it is right for each to think his and hers the best and most
delightful.
One afternoon the carriage set us down in so quiet a street that I
could hardly believe it was New York. And when I entered the house,
my new house, I doubted more than ever, for everybody was there.
One kissed me until I thought the breath of life was surely gone, then
another took me up. I have a dim suspicion that my sleeves were
worn threadbare, and if my hair had not been all fast in my head, I
am afraid the difference would have been discoverable.
“Why you are rounder and rosier than ever!” declared Fan,
inspecting me.
She was elegant as a princess, and had her light silk dress
trimmed with applique lace.
It seemed as if I never could get done looking at mamma, and
papa hovered around me as if I was indeed an unusual sight.
Somehow I managed to get up-stairs to my own pretty room, to
wash my face, what there was left of it, and straighten my gown. And
there was Beauty, my lovely half-grown kitten that some one had
brought from the old home.
I heard Stuart’s voice outside the door and called him in.
“Stuart,” I said with much dignity, “this is Miss Beauty Endicott, a
nice, orderly, well brought-up kitten, and mine. I want you to respect
her and treat her with the courtesy of a gentleman.”
“Oh, fudge!” he returned. “What are you doing with a kitten when
you are married? I thought it was only old maids who were death on
cats.”
“It is boys who are death on cats,” I replied severely. “And then—I
never did expect to be married. I always supposed—”
“Oh, you couldn’t have been an old maid! your nose never can be
sharp, and your chin has that great dimple in it, and you are such a
funny little dumpling altogether! If you say much I’ll put you in my
pocket and carry you off. No doubt Stephen would feel immensely
relieved, but what could the cat do?”
“You are an incorrigible boy!”
“But we will have jolly times for all that,” and he whistled to Tim,
who put her head within the door.
“Fan,” I exclaimed with remorseful tenderness as I was going
down stairs with her arm over my shoulder; “I have Mrs. Whitcomb.
But you know you half gave her to Stephen. And as you are not to
keep house—”
“I will lend her to you a little while longer.”
We had such a merry, enjoyable supper, such a lovely long
evening, and were brimfull of happiness.
But the next morning papa gathered up his flock, “what there was
left of them,” he said with a certain comical grimace.
“I don’t know as you need lament,” answered Stephen. “I think the
sons are coming in pretty rapidly.”
“And if there should be seven! Mother what would we do with them
all?”
Mamma smiled a little as Stephen went around and kissed her.
“Remember that I am the first one; I will never be crowded out of
my place.”
“No,” she answered softly.
They all went away that noon, and left us to begin our home life.
We had talked it over, what we were to do for the boys, what for
ourselves, and what for the world outside. For the true life is not
bounded with a narrow—thou and I. The world takes us in, and over
and above all, God takes us in. His vineyard, His day, and first and
always His everlasting love.
Young Folks’ Heroes of the Rebellion.
By Rev. P. C. HEADLEY.
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FIGHT IT OUT ON THIS LINE. The Life and Deeds of General U. S.

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The Glorious March to the Sea by the brave Sherman and his boys will never be
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FIGHTING PHIL. The Life and Military Career of Lieut-Gen. Philip
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The story of the dashing Cavalry General of the army of the United States.—A
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OLD SALAMANDER. The Life and Naval Career of Admiral David
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The Naval History of the great civil war is exceedingly interesting, and the life of
Admiral Farragut is rich in brave deeds and heroic example.
THE MINER BOY AND HIS MONITOR. The Career and
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One of the most thrilling incidents of the war was the sudden appearance of the
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OLD STARS. The Life and Military Career of Major-Gen. Ormsby
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“Old Stars” was the pet name given the brave general by his soldiers, who
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☞Sold by all booksellers, or sent by mail, postpaid, on receipt of

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LEE AND SHEPARD, Publishers, Boston.

YOUNG FOLKS’ HEROES OF HISTORY.
By GEORGE MAKEPEACE TOWLE.
Handsomely Illustrated. Price per vol., $1.25. Sets in neat boxes.
VASCO DA GAMA:
HIS VOYAGES AND ADVENTURES.
“Da Gama’s history is full of striking adventures, thrilling incidents, and perilous
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PIZARRO:
HIS ADVENTURES AND CONQUESTS.
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the conqueror of Peru. Not even King Arthur, or Thaddeus of Warsaw, has the
power to captivate the imagination of the growing boy. Mr. Towle has handled his
subject in a glowing but truthful manner; and we venture the assertion, that, were
our children led to read such books as this, the taste for unwholesome, exciting,
wrong-teaching boys’ books—dime novels in books’ clothing—would be greatly
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generation.”—Chicago Alliance.
MAGELLAN;
OR, THE FIRST VOYAGE ROUND THE WORLD.
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HIS TRAVELS AND ADVENTURES.
“The story of the adventurous Venetian, who six hundred years ago penetrated
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Sold by all Booksellers, and sent by mail, postpaid, on receipt of

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LEE & SHEPARD, Publishers BOSTON.

Transcriber’s Notes
pg 64 Changed: She smiled in her irresistable fashion,

to: She smiled in her irresistible fashion,
pg 128 Changed: papa would say,” was my rejoiner
to: papa would say,” was my rejoinder
pg 150 Changed: And she enjoys everything so thorougly.
to: And she enjoys everything so thoroughly.
pg 168 Changed: our engagements and geting everything
to: our engagements and getting everything
pg 183 Changed: Here were sandwitches dripping with jelly
to: Here were sandwiches dripping with jelly
pg 185 Changed: great double lucious blossoms
to: great double luscious blossoms
pg 208 Changed: with a certain funny lugubriouness
to: with a certain funny lugubriousness
pg 238 Changed: Dosn’t she take care of sick people
to: Doesn’t she take care of sick people
pg 264 Changed: nothing but complaint and discouragment
to: nothing but complaint and discouragement
pg 264 Changed: went to neigboring towns
to: went to neighboring towns
pg 274 Changed: I struck out blindy
to: I struck out blindly
pg 284 Changed: I have gussed
to: I have guessed
pg 285 Changed: It is not—Winthop Ogden.
to: It is not—Winthrop Ogden.
pg 287 Changed: bound by a promise of secresy
to: bound by a promise of secrecy
pg 300 Changed: no expensive trosseau
to: no expensive trousseau
pg 317 Changed: spoken of the probabilty
to: spoken of the probability
pg 337 Changed: It was the begining
to: It was the beginning

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Neurobiology of Autism Spectrum

Disorders 1st Edition Abdeslem El

Designing for Autism Spectrum Disorders Kristi Gaines

Encyclopedia of Autism Spectrum Disorders 2nd Edition

Autism Spectrum Disorders in Adults 1st Edition

Adolescents and Adults with Autism Spectrum Disorders

Neural Engineering Techniques for Autism Spectrum

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Handbook of Treatments for Autism Spectrum Disorder 1st

Technology and the Treatment of Children with Autism

ISBN 978-3-031-42382-6 ISBN 978-3-031-42383-3 (eBook)

Paper in this product is recyclable.

The human brain is a complex self-organizing system which depends on precise

contribute to the advancement of evidence-based practices that can improve the

New York, NY, USA Abdeslem El Idrissi

1 Dysfunctional Circuit Mechanisms of Sensory Processing

10 Prophylactic Treatment of ASD Based on Sleep-Wake Circadian

The art of being wise is knowing what to overlook

1.1 Sensory Processing and Decision Making

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

1.3 Mouse Models of Fragile X Syndrome and ASD

reduced habituation of sound-evoked responses (Lovelace et al., 2016), are seen

Presynaptic Network mechanisms

1.4 Sensory Processing Deficits in the Context

Sensory cortex undergoes a maturation and refinement during development which

1.5 Inhibition in the Neurotypical Sensory Cortex

Inhibition in the sensory cortex is mediated by three populations of interneurons–

and ASD, investigating how inhibitory neurons (and by association excitatory

1.6 Sensory Deficits in the Visual Domain

1.7 Sensory Deficits in the Auditory Domain

Atypical exaggerated responses to sounds and an inability to habituate to irrelevant

1.8 Sensory Deficits in Somatosensory Domain

The sensory deficits observed in Fmr1 KO mice prompted researchers to identify a

Choices are the hinges of destiny – Pythagoras.

mouse models have provided a valuable characterization of sensory, learning and

Golshani, P., et al. (2009). Internally mediated developmental desynchronization of neocortical

WISHED there could be no such thing as breakfast the

I cannot tell you anything about it, or Stephen. It was a happy

SIX VOLUMES. ILLUSTRATED. PER VOL. $1.25.

FIGHT IT OUT ON THIS LINE. The Life and Deeds of General U. S.

☞Sold by all booksellers, or sent by mail, postpaid, on receipt of

LEE AND SHEPARD, Publishers, Boston.

Sold by all Booksellers, and sent by mail, postpaid, on receipt of

LEE & SHEPARD, Publishers BOSTON.

pg 64 Changed: She smiled in her irresistable fashion,

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