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\begin{document}

\title{Development of Multisensory Processing in Ferret Parietal Cortex.}



\author[1]{Alexandre Medina}%
\author[2]{W. Alex Foxworthy}%
\author[1]{Dongil Keum}%
\author[3]{M. Alex Meredith}%
\affil[1]{University of Maryland Baltimore}%
\affil[2]{Eastern Shore Community College}%
\affil[3]{Virginia Commonwealth University}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
It is well known that the nervous system adjusts itself to its
environment during development. Although a great deal of effort has been
directed toward understanding the developmental processes of the
individual sensory systems (e.g., vision, hearing, etc.), only one major
study has examined the maturation of multisensory processing of cortical
neurons. Therefore, the present investigation sought to evaluate
multisensory development in a different cortical region and species.
Using multiple single-unit recordings in anesthetized ferrets (n=18) of
different ages (from postnatal day 80 through 300), we studied the
responses of neurons from the rostral posterior parietal area (PPr) to
presentations of visual, tactile and combined visual-tactile
stimulation. The results showed that multisensory neurons were
infrequent at the youngest ages (pre-pubertal) and progressively
increased through the later ages. Significant response changes that
result from multisensory stimulation (defined as multisensory
integration, MSI) were observed in post-pubertal adolescent animals and
the magnitude of these integrated responses also increased across this
age group. Furthermore, non-significant multisensory response changes
were progressively increased in adolescent animals. Collectively, at the
population level, MSI was observed to shift from primarily suppressive
levels in infants to increasingly higher levels in later stages. These
data indicate that, like the unisensory systems from which it is
derived, multisensory processing shows developmental changes the
specific time course of which may be regionally and species dependent.%
\end{abstract}%



\sloppy


\textbf{Development of Multisensory Processing in Ferret Parietal
Cortex.}

Alexandre E. Medina\textsuperscript{1}, W. Alex
Foxworthy\textsuperscript{2,3}, Dongil Keum\textsuperscript{1}, M. Alex
Meredith\textsuperscript{2}

1- Department of Pediatrics, University of Maryland, School of Medicine,
Baltimore, MD.

2- Department of Anatomy and Neurobiology, Virginia Commonwealth
University, Richmond, VA.

3- Department of Biology, Eastern Shore Community College, Melfa, VA.

Author contributions: Experimental design (AEM, MAM); Conducted
experiments (WAF, MAM); Data Analysis (AEM, MAM, DK); Wrote the
manuscript (AEM, MAM).

Correspondence should be addressed to:

Alexandre E. Medina, amedina@som.umaryland.edu

M. Alex Meredith, marvin.meredith@vcuhealth.org

Number of Figures: 6

Number of Tables: 2

Number of words for abstract: 225

Number of words for Introduction: 1099

Number of words for Discussion: 926

Authors do not have any conflict of interest.

Sharing of resources: All recording data and analyzes will be available
upon request.

Funding sources: Grant sponsor: National Institutes of Health; Grant
number: NS064675 (MAM); AA13023 (AEM).

\textbf{Abstract}

It is well known that the nervous system adjusts itself to its
environment during development. Although a great deal of effort has been
directed toward understanding the developmental processes of the
individual sensory systems (e.g., vision, hearing, etc.), only one major
study has examined the maturation of multisensory processing of cortical
neurons. Therefore, the present investigation sought to evaluate
multisensory development in a different cortical region and species.
Using multiple single-unit recordings in anesthetized ferrets (n=18) of
different ages (from postnatal day 80 through 300), we studied the
responses of neurons from the rostral posterior parietal area (PPr) to
presentations of visual, tactile and combined visual-tactile
stimulation. The results showed that multisensory neurons were
infrequent at the youngest ages (pre-pubertal) and progressively
increased through the later ages. Significant response changes that
result from multisensory stimulation (defined as multisensory
integration, MSI) were observed in post-pubertal adolescent animals and
the magnitude of these integrated responses also increased across this
age group. Furthermore, non-significant multisensory response changes
were progressively increased in adolescent animals. Collectively, at the
population level, MSI was observed to shift from primarily suppressive
levels in infants to increasingly higher levels in later stages. These
data indicate that, like the unisensory systems from which it is
derived, multisensory processing shows developmental changes the
specific time course of which may be regionally and species dependent.



\textbf{Introduction}

How the cerebral cortex organizes itself to analyze and perceive the
sensory world around it has been the topic of intense scrutiny for
decades now (e.g., see (Crain, 1952; Grossman, 1955; Eayrs \& Goodhead,
1959). In general, the course of neural sensory development has been
extensively examined from a unisensory perspective by evaluating
neuronal responses evoked by the presentation of stimuli from one
sensory modality. For example, development of cortical sensory responses
have been described for visual (Wiesel \& Hubel, 1963), somatosensory
(Rubel, 1971) and auditory (Kral \emph{et al.} , 2001) areas in a
variety of mammalian models from mice to non-human primates. From these
and numerous other studies, the general pattern of cortical sensory
development indicates that early postnatal responses are often
comparatively weak, with long response latencies, higher levels of
spontaneous activity and broad receptive fields regardless of the
modality involved. These features were found to progressively change
across postnatal development to eventually reach values consistent with
neurally mature adults. However, the brain does not habitate a
unisensory world and events commonly occur that are detected by more
than one sensory modality. Correspondingly, multisensory neurons have
been identified so frequently that it has been asserted that the
neocortex is ``essentially multisensory'' (Ghazanfar \& Schroeder,
2006).

Despite the ubiquitous presence of cortical multisensory neurons, few
studies of the development of cortical neuronal multisensory properties
have been published. A very early study of multisensory development
observed neurons in feline association (Lateral Suprasylvian area)
cortex that primarily responded unisensory stimulation early in the
postnatal period (e.g., 67\% at postnatal day 8), but were largely
replaced by multisensory neurons (89\%) by postnatal day (P) 50
(Mayers\emph{et al.} , 1971). This general multisensory developmental
sequence was reiterated for a different feline cortical region, the
Anterior Ectosylvian Sulcal cortex (AES), in a study by (Wallace
\emph{et al.} , 2006). Here, the functional onset for somatosensory
responsivity was present for the earliest age group (P28), auditory
onset occurred near P56 and the onset of the first multisensory neurons
(bimodal somatosensory-auditory) was also seen at that same time.
Further, visual response activity was first observed at P84 at which
time the first multisensory neurons with visual inputs were also
identified. Thus, although unisensory neurons had earlier functional
onsets than did multisensory ones, it seemed that once a particular
modality became active, its functional effect applied to both unisensory
and multisensory neurons. Furthermore, the time course of these
respective sensory onsets corresponded with the expression of specific
sensory guided behaviors (Larson \& Stein, 1984). The Wallace et al.
(2006) study went even further to examine the development of
multisensory integration (MSI), which is the effect that multisensory
neurons can generate when responding to concurrent stimulation from more
than one sensory modality. Even though bimodal neurons were identified
by P56, neurons that exhibited MSI were not observed until P84, after
which their incidence progressively increased into adulthood. However,
the magnitude of MSI response change did not change across this
developmental period, since the levels observed at early stages (e.g.,
P84) were essentially the same as those seen in adults. Thus, this study
(Wallace \emph{et al.} , 2006) revealed that multisensory features
develop gradually during maturation, but when they do they immediately
exhibited adult-like properties.

More recently, an additional form of multisensory neuron has been
identified that is different from the traditional bimodal (and trimodal)
types. This form, which responds to a single unisensory stimulus, but
has that response significantly modified by the presence of a stimulus
from a different modality, is termed a subthreshold multisensory neuron
(Dehner \emph{et al.} , 2004; Allman \& Meredith, 2007; Allman \emph{et
al.} , 2009). Like bimodal neurons, subthreshold multisensory neurons
can show multisensory response enhancement (as studied in (Wallace
\emph{et al.} , 2006)) as well as response depression (Dehner \emph{et
al.} , 2004). However, it is not known when these subthreshold
multisensory neurons occur developmentally nor has the developmental
time-course of multisensory response depression been reported. In
addition, multisensory neurons can respond to multisensory stimulation
without exhibiting MSI, but with responses that fail to achieve a
statistically significant difference from their most effective
unisensory response (e.g., see (Perrault Jr \emph{et al.} , 2005)). Such
non-significant response changes, however, can contribute to substantial
effects at the population level (Merrikhi \emph{et al.} , 2022a;
Merrikhi \emph{et al.} , 2022b) although their developmental
presentation is not known. Furthermore, the AES area is a conglomerate
region consisting of 3 different sensory representations, each with
their own connectional features and functional properties (for review,
see (Meredith \emph{et al.} , 2018)). Consequently, the developmental
effects for a singular multisensory cortical region, to our knowledge,
has not yet been described. Therefore, the present investigation seeks
to incorporate these recent details about multisensory processing into
an assessment of the development of multisensory processing within a
singular cortical region, the ferret Rostral Posterior Parietal cortex
(PPr).

Like many higher mammals, ferrets have a gyrencephalic brain,
demonstrate a high proportion of white matter (Schwerin \emph{et al.} ,
2017), and their visual cortices exhibit ocular and
orientation-selectively columns (Issa \emph{et al.} , 1999;
Medina\emph{et al.} , 2005). As a consequence, ferrets have been used to
examine amblyopia (Liao \emph{et al.} , 2004; Krahe \emph{et al.} ,
2005) or crossmodal plasticity (Roe \emph{et al.} , 1990) as well as in
neuropsychiatric and neurologic conditions such as Fetal Alcohol
Spectrum Disorders (Medina \emph{et al.} , 2003; Medina \emph{et al.} ,
2005; 2006; Paul \emph{et al.} , 2010; Keum \emph{et al.} , 2023), TBI
(Schwerin \emph{et al.} , 2017; Goodfellow \emph{et al.} , 2022) and
cortical dysplasia (Noctor \emph{et al.} , 1999; Abbah \& Juliano,
2014). The cortical location of the PPr is depicted on the lateral view
of the ferret brain shown in Figure 1A. This region has been
demonstrated to contain unisensory somatosensory and unisensory visual
neurons, as well as bimodal and subthreshold multisensory neurons
affected by those same sensory modalities (Manger \emph{et al.} , 2002;
Foxworthy \emph{et al.} , 2013; Foxworthy \emph{et al.} , 2014). The
receptive fields of these neurons are comparatively large, such that a
standardized stimulus set is effective in activating a large proportion
of sensory neurons within a multiple single-unit recording site. In
addition to ferrets, the parietal cortex is well studied in humans,
monkeys and rodents and behavioral involvements have been established
for the region in relation to attention, rectification of spatial maps,
goal-directed behaviors and self-awareness (Calton \& Taube, 2009; Nitz,
2009; Reep \& Corwin, 2009; Save \& Poucet, 2009; Alais \emph{et al.} ,
2010; Kaas \emph{et al.} , 2011; Blanke, 2012). Because all eutherians
studied reveal a multisensory visual--somatosensory region between
visual and somatosensory cortical representations (Manger \emph{et al.}
, 2002; Kaas, 2009), the properties of bimodal and unisensory neurons
observed in the ferret PPr can be generalizable to a wide number of
species.

\textbf{Methods}

Experiments were performed in compliance with the Guide for Care and Use
of Laboratory Animals (National Institutes of Health, publication
86-23), the National Research Council's Guidelines for Care and Use of
Mammals in Neuroscience and Behavioral Research (2003), and with
approval from the Institutional Animal Care and Use Committee at
Virginia Commonwealth University. Details of these procedures are
provided in a previous report (Foxworthy \emph{et al.} , 2013). Ferrets
were obtained from a licensed vendor (Marshall Farms, Inc.) and were
housed in VCU Department of Animal resources until used. All ferrets
were male and their age on the experiment day ranged from P80 -- P300.
Based on these ages, each ferret was assigned to one of four
developmental groups. (1) Infancy: ferrets less than P90 are weaned but
have not yet reached sexual maturity (have not yet become adolescents).
Next, because onset of sexual maturity can occur as early as 4 months of
age, animals aged \textgreater{}P120 are post-pubertal and were
considered (2) early adolescent (P120-155); (3) mid-adolescent
(P160-200) and (4) late adolescent (P240-P300). There is, as yet, no
consensus on when ferrets become neurologically mature adults.

For the recording experiments, the animal was anesthetized (8mg/kg
ketamine; 0.03mg/kg dexmedetomidine intramuscularly) and their head were
secured in a stereotaxic frame. A craniotomy was made to expose the
rostral posterior parietal (PPr) portion of the suprasylvian gyrus.
Across this opening a recording well/head supporting device was
implanted using stainless steel screws and dental acrylic to support the
head without obstructing the eyes or ears. The implant was then secured
to a supporting bar. The animals were intubated through the mouth,
ventilated (expired CO\textsubscript{2}: \textasciitilde{}4.5\%) and
immobilized (pancuronium bromide; 0.3 mg/kg initial dose; 0.2 mg/kg h
supplement i.p.) to prevent ocular drift or spontaneous limb movements
during testing. Fluids (lactated Ringer's solution) and supplemental
anesthetics (4mg/kg h ketamine; 0.5 mg/kg h acepromazine i.p.) were
administered continuously with an infusion pump. Heart rate was
monitored continuously, and body temperature was monitored and
maintained at \textasciitilde{}38\selectlanguage{ngerman}°C with a heating pad.

Within the craniotomy the dura was opened to identify the location of
the PPr (based on gyral patterns) and to insert the recording electrode
array. Neuronal activity was recorded using a four shank, 32-channel
silicon probe (A4×8-5mm 200--200-413 array; impedance \textasciitilde{}1
M\selectlanguage{greek}Ω; \selectlanguage{english}NeuroNexus Technologies, Ann Arbor, MI) as described in previous
reports (Allman \emph{et al.} , 2009; Keniston \emph{et al.} , 2009;
Foxworthy \emph{et al.} , 2013). Neuronal activity was digitized
(rate\textgreater{}25kHz) using a TDT System III Workstation
(TuckerDavis Technologies Alchua, FL) using MatLab software and archived
for off-line analysis. Spike waveforms were clustered by principal
component feature space analysis and sorted into individual units using
an automated Bayesian sort-routine. Spikes which exhibited interspike
intervals \textless{} 2ms were rejected.

Once PPr neurons were identified and templated, their responses to
sensory stimulation were assessed. Quantitative sensory testing
consisted of somatosensory stimuli produced by a calibrated 1-gram
monofilament fiber moved by an electronically-driven, modified shaker
that displaced hair or indented the skin. Visual stimulation consisted
of a bar or spot of light, whose movement direction, velocity, and
amplitude across the visual receptive field was computer-controlled and
projected onto the translucent hemisphere. These somatosensory and
visual stimuli were presented separately and in combination, and each
stimulus or combination was repeated 50 times (randomly interleaved with
3-7 second presentation interval). During combined presentations, the
onsets of the stimuli were offset by 40ms (visual preceded tactile) to
accommodate for the difference in response latency among these sensory
modalities. Attention was given to maintaining the consistency of
sensory stimulation between different experiments, such that the
somatosensory stimulus was always positioned on the contralateral side
of the face and moved at the same velocity and amplitude; visual
stimulation always consisted of a moving (150 \selectlanguage{ngerman}º/sec) bar (5x20º) of
light that crossed \textasciitilde{}45º of contralateral visual space in
the nasal-to-temporal direction.

Neuronal responses to somatosensory, visual, and combined
visual-somatosensory stimuli analyzed using custom software (MatLab;
described in (Allman \emph{et al.} , 2009; Keniston \emph{et al.} ,
2009). A neuronal response was defined as spiking activity which
exceeded 3 standard deviations from spontaneous activity, lasted for a
minimum of 15ms, and ended when activity returned to baseline for at
least 15ms. Neurons showing suprathreshold activation to individual
stimuli from more than one sensory modality were defined as bimodal
multisensory neurons. Neurons which showed suprathreshold activation by
only one modality but exhibited responses that were significantly
different in the combined stimulus condition than in the unisensory
stimulus condition (determined by t-test) were classified as
subthreshold multisensory neurons. However, neurons that were driven
exclusively by one modality and did not show change in responses after
combined stimulation were categorized as unimodal.

Multisensory (bimodal and subthreshold) neurons were further analyzed to
determine if they demonstrated integrated responses to multisensory
stimulation. Specifically, responses showing a significantly different
(assessed by t-test) activation (mean spikes/trial) to multisensory
stimuli versus that elicited by the most effective single modality
stimulus were defined as exhibiting multisensory integration (Meredith
\& Stein, 1983). Significant response increases were termed multisensory
response enhancement, while those showing a significantly reduced
activation were regarded as demonstrating multisensory response
depression (also called multisensory suppression (Keum \emph{et al.} ,
2023)). The magnitude of multisensory integration was calculated
according to the method of (Meredith \& Stein, 1986) using the formula:
(CM-SM\textsubscript{max})/ SM\textsubscript{max} x 100 = \%
Integration. In this equation, SM\textsubscript{max} was the neuron's
response to the most effective unisensory stimulus (mean spikes/trial)
and CM was the response to the multisensory stimulus. Ultimately, the
neuronal response type (unisensory, bimodal, subthreshold) as well as
the direction (enhancement, depression) and magnitude (\% response
change) of multisensory responses were tabulated in relation to the age
of the experimental animal.

Once the recording session was completed, the animal was overdosed
(Euthasol), perfused intracardially with saline and fixed (4\%
paraformaldehyde). The brain was blocked stereotaxically and the cortex
containing the recording site(s) was processed for histological
verification of the recording sites. Recording tracks confirmed within
the grey matter of the PPr were included in this study.

\textbf{Results}

The sensory and multisensory properties of neurons in PPr (Fig. 1A) were
electrophysiologically recorded in 18 male ferrets that ranged in age
from P80 to P300. A total of 538 PPr neurons were tested with visual,
tactile and combined visual-tactile stimulation presented in a random,
interleaved manner. Fig. 1B depicts the experimental setup. Recorded
neurons were grouped by their response patterns into the following
categories: unimodal visual (V), unimodal tactile (T), bimodal (VT) and
subthreshold multisensory (S). Fig. 1C shows representative examples of
PPr neurons from each of these categories. Neuronal responses defined as
multisensory integration (MSI) showed a statistically significant
response change (either depression or enhancement) evoked by a combined
visual-tactile stimulus when compared to that elicited by the most
effective unimodal cue (Meredith \& Stein, 1983). Examples of responses
showing MSI are illustrated in the raster/histograms shown in the middle
row of Fig. 1C. In addition, subthreshold multisensory responses are
defined as a statistically significant response change elicited by
combined visual-tactile stimulation when a neuron was activated by only
one sensory modality presented alone. Examples of such subthreshold
multisensory responses are shown in Fig. 1C (bottom row).

To evaluate the incidence and distribution of the different neuronal
categories during postnatal development, the sampled PPr neurons were
sorted by age-group. As defined in Methods, animals were divided by age
in the following groups: Infancy, (P80-P90; Neurons/Animals=49/2), Early
adolescence (P120-P155; 241/6), Mid adolescence (P160-P200; 179/6) and
Late adolescence (P240-P300; 69/2). As shown in Fig. 2, these results
show that, although each neuronal response type was observed in each age
group, their relative proportions systematically changed. Chi-square
tests (with Bonferroni corrections for multiple comparisons) showed that
the Infant group exhibited more unimodal V but fewer bimodal VT cells
than all the other groups (P\textless{}0.008). All other comparisons did
not reach significance. Figure 2B replots this same data to emphasize
the progressive change in the proportions of neurons in each response
category. From this it is evident that the proportions of unimodal V
cells markedly reduce from infancy to early adolescence and decrease
even further through late adolescence. In contrast, the number of
bimodal VT cells dramatically increase from infancy to early adolescence
and these numbers remain high through late adolescence. Likewise, the
incidence of the other form of multisensory neuron, the subthreshold
category, also proportionally increases steadily during development.

Next, the level of neuronal responsiveness across postnatal development
was examined. The average number of spikes evoked by sensory stimulation
was collated by age group, as illustrated in Fig. 3 and summarized in
Table 1. In general, response activity tended to increase from infant to
early adolescence but then decreased through late adolescence.

For unimodal neurons, responses were only significantly different
between early and mid-adolescence stages (univariate ANOVA, f = 4.7, p =
0.004; followed by post hoc Bonferroni test, p = 0.002). In bimodal
neurons, the early-adolescence group showed significantly higher
responses than all other age groups (univariate ANOVA, f = 7.2, p
\textless{} 0.001; followed by post hoc Bonferroni test; Early vs
Infancy, p = 0.03; Early vs Mid, p = 0.02; Early vs Late, p = 0.001). No
significant difference in responsiveness across ages was observed in
subthreshold neurons.

Next, we evaluated the rates of spontaneous activity over the course of
development. This was calculated by recording the number of spikes per
second fired during the 500ms interval before the onset of the sensory
stimulus for each age group. These results are illustrated in Fig. 4 and
summarized in Table 2.

No significant differences in spontaneous activity were observed between
age groups in unimodal and subthreshold neurons. In bimodal neurons, the
Late-adolescence group showed significantly higher spontaneous activity
(univariate ANOVA, f = 4, p = 0.008; followed by post hoc Bonferroni
test) than Early (p = 0.03) and Mid-adolescence (p = 0.004). That spike
rates are elevated in bimodal PPr neurons has been reported previously
(Foxworthy et al., 2014).

Next, we quantified the proportion of bimodal neurons that exhibited
significant MSI. No bimodal neurons showed integration during infancy
but, as shown in Figure 5A, the proportions of bimodal neurons that
exhibit MS enhancement gradually increase during development
(Infancy=none, Early=23\%, Mid=28\%, Late 67\%). Only a single example
of multisensory depression was observed among the bimodal neurons
sampled, which occurred in the early adolescence group. In the context
of the levels of MSI, an increase in the magnitude of response change
was observed from early to mid-adolescence and remained constant after
that. Figure 5B shows that the magnitude of enhancement was
significantly higher for bimodal neurons during mid- and
late-adolescence when compared to early. Kruskall-Wallis non-parametric
ANOVA showed significant differences (KW-H= 10.07, p \textless{}0.001).
Post Hoc Mann Whitney tests comparisons between groups showed
significant differences between Early vs Mid (Z= -2.87, p = 0.004) and
Early vs Late (Z= -4.21, p \textless{}0.001) but not Mid vs Late (Z =
-0.71, p = 0.48). Median response changes in these groups: Early=
32.7\%; Mid= 49.9\%; Late= 51.3\%.

Not all bimodal neurons exhibit MSI in response to effective
multisensory stimulation. Neurons presenting small changes in firing in
response to combined visual-tactile stimulation may fail to achieve the
statistical significance that defines MSI. Nevertheless, these
non-integrative responses contribute to the population response of an
area and small changes in response can collectively produce a major
change at the population level. Therefore, it seems conceivable that
population responses can reveal differences not observed when only
neurons that meet MSI criteria are considered (Keum \emph{et al.} ,
2023). Fig 5C shows response changes in bimodal neurons that failed to
show MSI. Importantly, these non-integrative response changes tended to
increase during development, such that the median value of multisensory
response change was: Infancy= 9.8\%; Early= 6.4\%; Mid= 13\%; Late=
15\%. Kruskall-Wallis non-parametric ANOVA showed that the differences
observed were significant (KW-H= 10.07, P\textless{}0.001). Post Hoc
Mann Whitney tests comparisons between groups showed significant
differences between Infancy Vs Mid (Z= -2, p = 0.037); Infancy Vs Late
(Z= -2, p= 0.036); Early Vs Mid (Z=-2.4, p =0.016); Early Vs Late (Z=
-2.4, p = 0.018).

A similar, progressive increase in magnitude of multisensory response
change is shown in Fig. 5D which displays cumulative probability curves
of the multisensory response change measured for all bimodal neurons
(integrative and non-integrative) from the different age groups. In this
figure, a value of zero indicates that the combined visual-tactile
stimulation resulted in a number of spikes that was equal to the most
effective unimodal stimulus, while positive and negative values indicate
increases or decreases in response changes, respectively, regardless of
statistical significance. The cumulative response curves shown in Figure
5D consistently shift upwards from infancy to late adolescence. A
Kruskall-Wallis non-parametric ANOVA (KW) followed by post-hoc
Kolmogorov-Smirnov tests showed that all groups were significantly
different from each other (p\textless{}0.05 for all comparisons).

Last, we evaluated the development of subthreshold multisensory neurons
(Fig. 6). Only a single subthreshold neuron was observed within the
infant age-group (which showed MS enhancement), while progressively more
examples of subthreshold responses were observed during the adolescent
periods (Early, 3.3\% of PPr neurons; Mid, 7.6\%; Late 12.5\%; also
illustrated in Figure 2B). For all subthreshold responses to combined VT
stimulation, the median magnitude of multisensory response change during
the adolescent periods are shown in Figure 6A: Early (41\%), Mid (64\%),
Late (54\%) with no statistical significance observed between these
groups. Overall, subthreshold multisensory responses were most
frequently enhanced while only a few showed response depression (Early:
3 out of 14 neurons with an average depression of -29\%±4.2; Mid: 1 out
of 14 neurons that showed a depression of -22\%). Figures 6B and C
summarize the levels of multisensory enhancement and multisensory
depression, respectively, observed in subthreshold neurons; no
statistical differences in proportion or effects were observed between
these age groups.

\textbf{DISCUSSION}

These results show that multisensory neurons are present in ferret PPr
cortex at developmental stages that precede sexual maturity
(\textless{}\textasciitilde{}P120). Designated as the ``infant'' period,
multisensory neurons at that time, however, were the minority of neurons
observed and only one showed MSI (which was the singular subthreshold
neuron identified in this age group). At this early developmental stage,
these data from infant, pre-pubertal ferrets closely resemble findings
in cat cortex (Wallace \emph{et al.} , 2006), as well as superior
colliculus (Wallace \& Stein, 1997), where early multisensory neurons
respond independently to stimulation from more than one sensory modality
but fail to integrate responses when those cues are presented together.
Thus, despite the presence of multisensory convergence, the capacity to
integrate multisensory responses apparently is not yet developed in such
young cats or ferrets.

For the series of older ferrets (e.g., \textgreater{}P120), the presence
of multisensory neurons progressively increased, as was also seen in
developing cats following the epoch in which the first multisensory
neurons appeared (Wallace \emph{et al.} , 2006). In the present study,
this period is referred to as ``adolescence'' because, like
post-pubertal humans, neural development continues beyond the age of
sexual maturity. It is well known that neural maturity in humans is
delayed for approximately a decade after sexual onset, especially for
higher-order regions, such as inferior parietal and frontal cortices
(Spear, 2000a; Spear, 2000b). To our knowledge such conditions have not
yet been identified in ferrets (or cats) and hence, there is ambiguity
in what is actually defined as being neurally adult in these animals.
Indeed, the study of multisensory development in cats did not define
neural adulthood, except that the cats designated as adults were older
than P180, which is the age of sexual maturity for cats. As a
consequence, all the developmental age groups studied in cats were
pre-pubertal (Wallace \emph{et al.} , 2006). In contrast, the ferret age
groups in which MSI appeared and developed in bimodal neurons were all
post-pubertal adolescents. These conflicting results may be accounted
for by the species and methodological differences between these studies,
but it might also be possible that PPr neurons mature more slowly than
those of the AES perhaps as a reflection of cortical hierarchical
differences.

Further evidence that multisensory changes occur in PPr during the
ferret adolescent stages comes from the observation that multisensory
integration increases in magnitude after the age of sexual maturity at
\textasciitilde{}P120. Figure 2B summarizes this feature for bimodal
neurons that exhibit MSI, and significant increases in multisensory
enhancement were demonstrated for stages of adolescence at ages P160-200
and P200-240. Similar developmental increases in multisensory
enhancement have also been reported in another study of PPr neurons in
early alcohol-treated and control ferrets (Keum \emph{et al.} , 2023).
However, these data do not mirror the MSI levels reported for cats,
where the magnitude of multisensory response change observed during
development was not different from that seen in adults (Wallace \emph{et
al.} , 2006). It seems possible that these differences in results may be
accounted for by the species, regional and methodological differences of
these studies.

The present study also examined the levels of multisensory response
change that were not significantly different from the most effective
unisensory stimulus. It must be kept in mind that these non-integrative
responses were evoked in bimodal neurons that were individually
activated by visual and by somatosensory stimulation. As a consequence,
both stimuli were effective when presented alone and, by definition,
were presented within their excitatory receptive fields. Thus, the
observed non-integrative effects could not have been induced by
inhibitory effects of one stimulus being presented outside of its
receptive field. Numerous reports have documented and examined
non-integrated multisensory responses in bimodal neurons in a variety of
neural areas (Perrault Jr \emph{et al.} , 2005; Meredith \emph{et al.} ,
2021; Merrikhi \emph{et al.} , 2022a; Merrikhi \emph{et al.} , 2022b).
The present study shows that such non-integrative multisensory effects
were strongly influenced by development because, as depicted in Figure
5D, significant shifts were seen from primarily suppressive levels in
infants to progressively higher levels of multisensory response change
across the periods of adolescence. Furthermore, similar developmental
shifts in non-integrative responses were observed a separate study of
PPr neurons (Keum \emph{et al.} , 2023). Ultimately, the present results
show that both non-integrative and integrative response modes of bimodal
neurons change during post-pubertal development.

We also examined the subthreshold form of multisensory neuron across the
different age groups. Although small in occurrence (as also observed in
other areas -- (Meredith \emph{et al.} , 2021; Merrikhi \emph{et al.} ,
2022a; Merrikhi \emph{et al.} , 2022b), their proportions showed an
increasing trend during development but no developmental pattern for
changes in MSI levels were demonstrated. A similarly low incidence of
multisensory response depression revealed the presence of the effect
during development, but consistent changes across development could not
be assessed.

In summary, the present study in ferret cortical area PPr identified
patterns of appearance of multisensory neurons during development that
were similar to those reported for cat cortex (Wallace \emph{et al.} ,
2006). However, unlike the cat AES regions, the magnitude of MSI in
ferret PPr significantly increased across the post-pubertal
developmental stages. Furthermore, bimodal neurons whose multisensory
responses were not integrated showed a consistent shift from suppression
in infants to progressively higher levels of multisensory response chage
at the adolescent stages. These data, combined with the small presence
of subthreshold multisensory neurons give insight into how the
population of PPr neurons changes their responses to multisensory cues
across pre- and post-pubertal development. How these changes,
particularly during adolescence, are parlayed into the behavioral and
perceptual tasks of the region are clearly a topic for future
investigation.

ACKNOWLEDGMENTS:

Grant sponsor: National Institutes of Health; Grant number: NS064675
(MAM); AA13023 (AEM).

\textbf{Figure legends}

\textbf{Fig. 1} : (A) Lateral view of the ferret cerebral cortex
displaying the rostral posterior parietal cortex (PPr). The box shows
the enlarged PPr area below, with the large dots representing the
location of recording penetrations (not all displayed due to overlap).
(B) The experiment involved multiple single-unit recordings of responses
evoked by the presentation of a visual (white bar moved
nasal-to-temporal across a screen), a tactile stimulus (1 g calibrated
fiber moved across skin/hairs by an electronically controlled actuator),
or the combination of both visual and tactile stimulation. (C) Examples
of single-unit neuronal responses recorded after visual alone, tactile
alone and combined visual- tactile stimulation. Top row shows the
responses of a unimodal visual neuron (left) and a unimodal tactile
neuron (right). The middle row depicts a bimodal PPr neuron that
generated multisensory enhancement (left) (combined response
significantly greater than most effective unimodal response) and another
bimodal neuron (right) that generated multisensory response depression.
Bottom row shows a subthreshold multisensory response where a combined
stimulus significantly enhances (left) or depresses (right) activity
with a stimulus from a different modality that is not effective when
presented alone.

\textbf{Fig. 2.} Sensory and multisensory neurons in PPr show
proportional changes from infancy and across adolescence. (A) The
histograms indicate the average (± SE) proportion of a particular neuron
response type (V=unimodal visual; T=unimodal tactile; S=Subthreshold
multisensory; B=bimodal multisensory) during the different developmental
epochs (yellow=infancy; blue=early adolescence; green=middle
adolescence; red=late adolescence; see Methods for definitions). (B) The
same data as in part `A' except now plotted with lines connecting the
different response types across development.

\textbf{Fig. 3} : Responsiveness (average number of spikes/response ±
SE) of PPr neuron types (Unimodal =unisensory visual and unisensory
tactile; Bimodal multisensory; Subthreshold multisensory) across
developmental stages (Infancy=yellow; early adolescence=blue; middle
adolescence=green; late adolescence- red). For subthreshold neurons,
only one subthreshold such neuron was identified in infancy. Univariate
ANOVA followed by posthoc Bonferroni tests * = p\textless{}0.05; ** =
p\textless{}0.01.

\textbf{Fig. 4} : Spontaneous activity (spikes/sec ± SE; recorded 500 ms
before sensory stimulation) in unimodal (unisensory visual and
unisensory tactile), bimodal multisensory and subthreshold multisensory
neurons across the developmental periods (Infancy=yellow; early
adolescence=blue; middle adolescence=green; late adolescence=red). For
the subthreshold category, only one neuron was identified in infancy.
Univariate ANOVA followed by posthoc Bonferroni tests* =
p\textless{}0.05; ** = p\textless{}0.01.

\textbf{Fig. 5: A. Responses of PPr neurons to multisensory stimulation
across the developmental stages. (A) Pie charts indicate the p}
roportions of bimodal neurons that exhibited significant multisensory
integration in the different age groups. \textbf{B} . For bimodal
neurons that demonstrate MSI, these box/whisker plots show the
significant increase in the magnitude of MS enhancement. No enhancement
was seen during Infancy; the Early adolescence group was significantly
different from Mid and Late adolescence ones. KW followed by Post Hoc
Mann Whitney tests, p\textless{}0.01 in both comparisons. Mid and Late
adolescence groups were not different from each other. \textbf{C.} For
bimodal neurons that failed to demonstrate significant MSI, these
box/whisker plots show the significant increase in response levels
across the developmental stages. KW followed by Post Hoc Mann Whitney
tests, * = p\textless{}0.05. \textbf{D.} Cumulative probability plots of
response changes after combined VT stimulation in all bimodal neurons
(integrative and non-integrative) across four age groups. A
Kruskall-Wallis non-parametric ANOVA (KW) followed by post-hoc
Kolmogorov-Smirnov tests showed that all groups were significantly
different from each other (p\textless{}0.05 for all comparisons). These
data show that both integrative and non-integrative bimodal responses
exhibit developmental changes that shift from primarily suppressive
responses in neurons from infants to progressively higher response
changes in adolescents.

\textbf{Fig. 6:} (A) For all subthreshold multisensory neurons, although
present in each age group, their multisensory responses (box/whisker
plots for each age group) do not show significant changes in magnitude
across the different developmental stages. KW non-parametric ANOVA. Not
significant. Only a single subthreshold neuron was observed during
infancy (yellow circle). \textbf{B.} For subthreshold multisensory
neurons that exhibited response enhancement, the bar graphs (± SE) show
that the average magnitude of multisensory enhancement was not affected
by developmental age. (Univariate ANOVA. Not significant).
\textbf{C.}For subthreshold multisensory neurons that exhibited response
depression, the bar graphs (± SE) show that the average magnitude of
multisensory depression also was not affected by developmental age
(Univariate ANOVA; Not significant).

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