**5. Methods and procedures**

function of the *stage of learning*, toward a *complete functional specialization* in terms of either *encoding* or *retrieval* after consolidation. Several distinct patterns of this learning evolution *within* each of the patches (see, e.g., in **Figure 1**, top panel) implied a complex reorganization of the object processing sub-networks throughout both the *training* and the following *consolidation* period.

While there have been many cross-sectional comparisons of blind and sighted capabilities, the only research focused on *interventions* to enhance basic spatial-cognition abilities in people with blindness has been that based on my Cognitive-Kinesthetic drawing training. This intervention has been shown to improve *spatial memory* and *memory-guided spatiomotor coordination* to a dramatic extent. Although it is typically assumed that drawing is dependent on vision, previous work indicates that individuals with congenital blindness are able to learn to draw over some unspecified time period that often may take years [28–30]. My studies have shown, however, that everyone—blind, sighted, or visually impaired—can learn this skill in only a few hours through an appropriate training, such as the Cognitive-Kinesthetic methodology

I have further hypothesized that the improvements from the Cognitive-Kinesthetic training would *transfer*, or—*generalize,* to a wide range of *untrained* basic spatial-cognition abilities that extend well beyond the drawing task *per se* [6]. "Basic" abilities were conceptualized as those that are foundational to other tasks, such as the ability to perceive, and remember object features, textures, spatial configurations, and patterns, together with abilities for spatial analysis and new concept learning. My rationale for this *transfer of learning*, or *Generalization of Learning,* hypothesis derived from the fact that the act of drawing complex images from memory "orchestrates" multiple spatial-cognition abilities [2–3, 31–33]. A recent study confirmed my Generalization of Learning Hypothesis [34] by showing significant improvements in a large standardized battery of untrained cognitive tests [35–36] for the blind and low vision following the 10 hours of Cognitive-Kinesthetic training in a cohort of congenitally blind and

In the earlier cited studies, the Cognitive-Kinesthetic Drawing Training was designed and applied as a noninvasive intervention for a rapid enhancement of *spatial memory*, *spatial cognition* in general, and precise *memory-guided motor control* in both the blind and the sighted. The memory drawing protocol in the form developed for this training, fully engages the whole *perception-cognition-action loop* [3–4], which was a key element of my *conceptual framework* underlying the training. (Note here the expansion of the traditional "perception-action" loop to include the central component of "cognition" (**Figure 2**), as I believe it is critical to its gen-

**4. Switching of handedness as a form of learning effect?**

eralization to the gamut of spatial-cognition abilities.)

**3. Generalization of drawing-learning effects**

70 Neuroplasticity - Insights of Neural Reorganization

[3–4, 31–33].

severe low-vision participants.

#### **5.1. Participant and the Cognitive-Kinesthetic Training**

The participant was a 57-year-old male who had full vision until age of 47, when his vision began declining in one eye and then the other, and he was diagnosed with Leber's hereditary optic neuropathy. Within a year, he was blind, seeing only some light in the far periphery. He had been left-handed since birth. The participant gave informed consent for the experimental protocol, which was approved by the Smith-Kettlewell Institutional Review Board as in full conformance with the Declaration of Helsinki.

After only a total of 10 hours of the Cognitive-Kinesthetic Drawing Training (2 hours/day for 5 days [3]), this left-handed blind participant learned to develop detailed and robust *memory representations* of *haptically* explored (with the *preferred/left* hand) raised-line depictions of complex images, such as human faces and objects, in order to draw them with his *nonpreferred/right* hand. Thus, in order to generate the structured motor output of the drawing, he had to learn how to use these enhanced haptic memory representations to *replace* his *lost "eye-hand coordination"* by a *"memory-hand coordination"* mechanism now that he was blind.

In the process, this blind participant learned to *draw freely* with his *non-preferred/right* hand, guided *solely* by the haptic memory acquired with the other hand. This man had never been able to draw well even with his preferred/left hand while still sighted, so he and his family were greatly surprised by this successful outcome.

*I never could draw very well … That's why it's very interesting to me that I would've been the person that did not have drawing skills before, and to be able to do something like this now .., wow, it is exciting - you have thought me drawing better than I could when I could see … and - to do this with my right hand …!.*

In an additional session, he subsequently practiced drawing the *already* memorized images with his preferred/left hand.

**5.3. Innovative experimental platform**

comfortable padding around all sides to minimize movement.

**5.4. Brain imaging data acquisition and preprocessing**

**the assessment of brain plasticity changes**

The overall experimental platform integrated a number of innovations, such as, a *multisensory magnetic resonance (MR)-Compatible Tablet system*, and a novel type of parametric brain mapping—*Categorical-Change Maps* [37] that we developed especially for the purpose of assessing *brain plasticity changes* as a result of a causal intervention, and the *Cognitive-Kinesthetic Training*. The custom MR-Compatible Tablet system (**Figure 3**) allows for participant-controlled tactilestimulus presentation for haptic exploration and drawing in the scanner. This system consists of a plexiglass lectern extending across the participant's lap, topped with a dual-slot height-adjustable surface [3]. In the left slot was the raised-line drawing stimulus to be haptically explored during the *HE* task, and in the right slot was an MR-compatible electronic drawing tablet (EMS Medical Systems, Bologna, Italy) to be used during the *MD* and *S* tasks. Between scans, the participant was instructed how to remove the topmost raised-line drawing stimulus (which was just explored and drawn) from the left slot and place it by their side, exposing the next stimulus in the prescribed sequence. Participants used a plastic stylus to draw and scribble, with the movement of the stylus across the drawing tablet being recorded and presented in real time to the experimenters on a display in the control room. Auditory cues were presented through MR-compatible headphones (Resonance Technologies, Salem, MA). Our custom MR-compatible tablet system allowed participants to draw comfortably on the plastic lectern across their torso/lap without moving their head. Additionally, during scanning, the participant's head was stabilized in the head coil with firm but

Brain Reorganization in Late Adulthood: Rapid Left-to-Right Switch of Handedness…

http://dx.doi.org/10.5772/intechopen.76317

73

Functional MRI data were collected on a Siemens Trio 3 T magnet equipped with a 12-channel head coil (Siemens Healthcare, Erlangen, Germany). BOLD responses were obtained using an echo-planar (EPI) acquisition (TR = 2 s, TE = 28 ms, flip angle = 80<sup>o</sup>

size = 3.0 × 3.0 × 3.5 mm) consisting of 35 axial slices extending across the whole brain. Preprocessing was conducted using FSL (FMRIB Analysis Group, Oxford, UK) and included slice-time correction and two-phase motion correction, consisting of both within-scan and between-scan six-parameter rigid-body corrections. To facilitate segmentation and registration, a whole-brain high-resolution T1-weighted anatomical scan was also obtained for each participant (voxel size = 0.8 × 0.8 × 0.8 mm). White matter segmentation in this T1 scan was conducted using FreeSurfer (Martinos Center for Biomedical Imaging, Massachusetts General Hospital) and gray matter was generated with the mrGray function in the mrVISTA software package (Stanford Vision and Imaging Science and Technology, Palo Alto, USA). The Stanford package mrVISTA allows us to estimate the neural activation amplitudes for each task within respective regions of interest (ROIs) using a standard general linear model (GLM) procedure

for each task regressor applied to the average signal across all voxels within each ROI.

**5.5. Categorical-Change parametric mapping: a novel concept and methodology for** 

In studies on brain plasticity, it is critical to be able to fully assess functional brain *changes* due to either an intervention, a natural development, or other causes, such as loss of vision.

, voxel

#### **5.2. Experimental design**

A key component of the study was measuring whole-brain functional MRI (fMRI) activation before and after applying the Cognitive-Kinesthetic Drawing Training, allowing us to determine the neuroplastic changes in a *causal* framework (**Figure 3**).

As in previous studies with the Likova Cognitive-Kinesthetic training method, fMRI was run *before* and *after* the training for a battery of *raised-line* models of faces and objects as the drawing targets in a three-task block fMRI design [3–4]. The three tasks were as follows: *Haptic Exploration* (*HE*) involving perceptual exploration and encoding in memory of the raised-line model to be drawn; *Memory Draw* (*MD*)—the task to draw this model freehand, guided solely by the encoded haptic memory; *Scribble* (*S*) was a negative memory-control and motor-control task for the hand movements alone. Each task duration was 20 s, with a 20-s baseline condition (*Rest*, *R*) intervening between tasks. Importantly, as opposed to the usual null periods, the participant not only rested motionless but was also instructed and practiced to clear any memory or imagery from awareness ("*blank-mind*"). The start of each task or rest interval was prompted by an auditory cue. The whole task sequence with interleaved rest intervals (*R, HE, R, MD, R, S, R*) was repeated 12 times in each 1.5-hour fMRI session using a new face or object image for each repeat. The *HE* task was always performed with the preferred/left hand. The *MD* and *S* tasks were performed with the non-preferred/right, and additionally, with the preferred/left hand in separate scans.

**Figure 3.** Experimental design. The rapid Cognitive-Kinesthetic drawing training (2 hours/day × 5 days) was preceded and followed by fMRI scans. In the scanner, three tasks were performed in a block paradigm: *Haptic Exploration, Memory Draw*, and *Scribble.* Each task and interleaved rest period were 20 s in duration. An innovative MRI-compatible lectern (lower left) provided for tactile stimulus presentation and both nonvisual and visual drawing. Functional brain activation is color coded in red (lower right).

#### **5.3. Innovative experimental platform**

In an additional session, he subsequently practiced drawing the *already* memorized images

A key component of the study was measuring whole-brain functional MRI (fMRI) activation before and after applying the Cognitive-Kinesthetic Drawing Training, allowing us to deter-

As in previous studies with the Likova Cognitive-Kinesthetic training method, fMRI was run *before* and *after* the training for a battery of *raised-line* models of faces and objects as the drawing targets in a three-task block fMRI design [3–4]. The three tasks were as follows: *Haptic Exploration* (*HE*) involving perceptual exploration and encoding in memory of the raised-line model to be drawn; *Memory Draw* (*MD*)—the task to draw this model freehand, guided solely by the encoded haptic memory; *Scribble* (*S*) was a negative memory-control and motor-control task for the hand movements alone. Each task duration was 20 s, with a 20-s baseline condition (*Rest*, *R*) intervening between tasks. Importantly, as opposed to the usual null periods, the participant not only rested motionless but was also instructed and practiced to clear any memory or imagery from awareness ("*blank-mind*"). The start of each task or rest interval was prompted by an auditory cue. The whole task sequence with interleaved rest intervals (*R, HE, R, MD, R, S, R*) was repeated 12 times in each 1.5-hour fMRI session using a new face or object image for each repeat. The *HE* task was always performed with the preferred/left hand. The *MD* and *S* tasks were performed with the non-preferred/right, and additionally, with the

**Figure 3.** Experimental design. The rapid Cognitive-Kinesthetic drawing training (2 hours/day × 5 days) was preceded and followed by fMRI scans. In the scanner, three tasks were performed in a block paradigm: *Haptic Exploration, Memory Draw*, and *Scribble.* Each task and interleaved rest period were 20 s in duration. An innovative MRI-compatible lectern (lower left) provided for tactile stimulus presentation and both nonvisual and visual drawing. Functional brain

mine the neuroplastic changes in a *causal* framework (**Figure 3**).

with his preferred/left hand.

72 Neuroplasticity - Insights of Neural Reorganization

preferred/left hand in separate scans.

activation is color coded in red (lower right).

**5.2. Experimental design**

The overall experimental platform integrated a number of innovations, such as, a *multisensory magnetic resonance (MR)-Compatible Tablet system*, and a novel type of parametric brain mapping—*Categorical-Change Maps* [37] that we developed especially for the purpose of assessing *brain plasticity changes* as a result of a causal intervention, and the *Cognitive-Kinesthetic Training*.

The custom MR-Compatible Tablet system (**Figure 3**) allows for participant-controlled tactilestimulus presentation for haptic exploration and drawing in the scanner. This system consists of a plexiglass lectern extending across the participant's lap, topped with a dual-slot height-adjustable surface [3]. In the left slot was the raised-line drawing stimulus to be haptically explored during the *HE* task, and in the right slot was an MR-compatible electronic drawing tablet (EMS Medical Systems, Bologna, Italy) to be used during the *MD* and *S* tasks. Between scans, the participant was instructed how to remove the topmost raised-line drawing stimulus (which was just explored and drawn) from the left slot and place it by their side, exposing the next stimulus in the prescribed sequence. Participants used a plastic stylus to draw and scribble, with the movement of the stylus across the drawing tablet being recorded and presented in real time to the experimenters on a display in the control room. Auditory cues were presented through MR-compatible headphones (Resonance Technologies, Salem, MA). Our custom MR-compatible tablet system allowed participants to draw comfortably on the plastic lectern across their torso/lap without moving their head. Additionally, during scanning, the participant's head was stabilized in the head coil with firm but comfortable padding around all sides to minimize movement.

#### **5.4. Brain imaging data acquisition and preprocessing**

Functional MRI data were collected on a Siemens Trio 3 T magnet equipped with a 12-channel head coil (Siemens Healthcare, Erlangen, Germany). BOLD responses were obtained using an echo-planar (EPI) acquisition (TR = 2 s, TE = 28 ms, flip angle = 80<sup>o</sup> , voxel size = 3.0 × 3.0 × 3.5 mm) consisting of 35 axial slices extending across the whole brain. Preprocessing was conducted using FSL (FMRIB Analysis Group, Oxford, UK) and included slice-time correction and two-phase motion correction, consisting of both within-scan and between-scan six-parameter rigid-body corrections. To facilitate segmentation and registration, a whole-brain high-resolution T1-weighted anatomical scan was also obtained for each participant (voxel size = 0.8 × 0.8 × 0.8 mm). White matter segmentation in this T1 scan was conducted using FreeSurfer (Martinos Center for Biomedical Imaging, Massachusetts General Hospital) and gray matter was generated with the mrGray function in the mrVISTA software package (Stanford Vision and Imaging Science and Technology, Palo Alto, USA). The Stanford package mrVISTA allows us to estimate the neural activation amplitudes for each task within respective regions of interest (ROIs) using a standard general linear model (GLM) procedure for each task regressor applied to the average signal across all voxels within each ROI.

#### **5.5. Categorical-Change parametric mapping: a novel concept and methodology for the assessment of brain plasticity changes**

In studies on brain plasticity, it is critical to be able to fully assess functional brain *changes* due to either an intervention, a natural development, or other causes, such as loss of vision.

**Figure 4.** Color coding for Categorical-Change mapping in the case of *positive baseline* activation. *Orange*: No significant change; *Red*: Reduced but still positive activation; *Yellow*: Increased positive activation; *Black*: Lost activation; *Blue*: BOLD signal inverted from positive into negative.

We have conceptualized a system of *brain-change categories* and developed a novel type of voxel-wise parametric mapping that can provide the needed *multifaceted assessment of neuroplasticity* [37], and thus, bridge a major gap in this field. This is based on (1) assessing the activation (in each voxel of the brain) during an initial state (e.g., *before* training; *baseline*) and (2) the change in activation (e.g., *after* training) *relative* to that baseline.

In the current study, we employed a subset of the categorical-change mapping to visualize **at once** *all five possible categories* of post-training change (or lack thereof) of any *positive baseline* activation prior to the state change or intervention.

The color coding for novel type of maps is shown in **Figure 4**. If an activated region did not undergo any significant change relative to the initial state, it is visualized in orange; if its positive activation was increased—in yellow; if it was reduced but still positive—in red; if the activation was lost—in black; while if the sign of the BOLD signal was inverted from positive into negative reflecting a changed in the nature of processing, it is shown in blue.

Note that we have developed the categorical-change mapping to assess the *full spectrum of possible changes*, relative to a given pre-intervention state. In other words, this mapping tool can also be applied to brain regions that in the *baseline* state have *negative* BOLD signal, or have *no activation* at all. These two options are beyond the scope of the present analysis, however.
