HD-tDCS as a Neurorehabilitation Technique for a Case of Post-Anoxic Leukoencephalopathy

Abstract

Post-anoxic leukoencephalopathy is a rare event that causes global demyelination secondary to anoxic injury. Given the nature and extent of the damage, cognitive and functional deficits are typically chronic even after standard therapies. Here, we describe a novel treatment approach that used high definition transcranial direct-current stimulation (HD-tDCS) with a 62-year-old male who was 5 years post-anoxic leukoencephalopathy secondary to an accidental drug overdose. HD-tDCS was administered over the left lateral prefrontal cortex across 29 daily sessions at 2 mA (20 minutes/session) in order to address dysexecutive behaviors. Results demonstrated improved delayed memory and trends for improved visuospatial and semantic fluency performance as well as improved insight and daily functioning, all of which returned to baseline by the end of a 10 week no-contact follow up period. Resting state fMRI connectivity results mirrored these changes by showing increased dorsal attention and cingulo-opercular but reduced ventral attention network connectivity after session 29, all of which returned to baseline at follow-up. These findings suggest HD-tDCS may benefit functioning even following serious and pervasive anoxic injury. Findings also suggest the need for continued HD-tDCS for maintenance purposes, though future work is needed to identify optimal dose-response information.

Introduction

Neuropathology of Post-Anoxic Leukoencephalopathy

Anoxic brain injury results from either lower circulating arterial oxygen or reduced cerebral perfusion. Anoxia initiates numerous complex changes in neuronal functioning, and the amount and length of oxygen deprivation greatly influences the extent of brain injury (Caine & Watson, 1998). In the event of reduced oxygen to the brain, dilation of blood vessels temporarily maintains blood flow and allows tissue to continue receiving adequate oxygen. However, in prolonged anoxic conditions membrane depolarization, influx of uncontrolled calcium, and activation of phospholopases and proteases lead to cell swelling and eventual cell death (Victor & Ropper, 2001; Michaels, 2004). While injury occurs on a whole-brain level, specific areas of the brain such as watershed territories and those with high metabolic demands (e.g., hippocampus, basal ganglia, cerebellum, thalamus) are more vulnerable to the effects of anoxic injury (Anderson & Arciniegas, 2010; Caine & Watson, 1998).

Post-anoxic leukoencephalopathy (PAL) can occur in more severe cases of anoxia and is a rare condition in which patients show initial recovery, sometimes returning to their baseline status, only to later show clinical decline consistent with hypoxic/anoxic injury days or weeks later (Shprecher & Mehta, 2010; Thacker et al., 1994). PAL causes damage to the brain via global demyelination, though typically sparing the cerebellum and brainstem (Shprecher & Mehta, 2010). While PAL etiology is unknown (Shprecher & Mehta, 2010; Zamora et al., 2015), it has been reported in those who experienced benzodiazepine and opiate overdose (Peter et al., 2004; Salazar & Dubow, 2012), carbon monoxide poisoning, complications from surgical anesthesia, and cardiac arrest (Shprecher & Mehta, 2010).

PAL Clinical Presentation

Given the widespread injury that occurs with PAL, it is unsurprising that cognitive deficits have been reported in virtually all domains including attention, language, executive function, and learning and memory (Anderson, & Arciniegas, 2010; Shprecher & Mehta, 2010; Victor & Ropper, 2001). Associated personality and behavioral changes can be wide-ranging but often include emotional lability, impulsivity, and irritability (Anderson, & Arciniegas, 2010). In more severe cases, PAL can also lead to frontal release signs and symptoms typically seen in psychosis (Shprecher & Mehta, 2010).

Recovery of cognitive, motor, and behavioral factors after PAL typically occur within the first year, with limited recovery in more severe cases (Smania et al., 2011; Victor & Ropper, 2001). While the length of coma and the patient’s functional ability upon admission may serve as good predictors of prognosis following “standard” anoxia (Heinz & Rollnik, 2015), comparatively little is known about recovery from PAL. However, most patients who experience PAL are left with chronic deficits even after standard therapeutic options such as speech, occupational, and physical therapy have been exhausted (Anderson & Arciniegas, 2010; Thacker, Asthana, & Sakari, 1994). It is within this context that we considered a form of non-invasive brain stimulation, transcranial direct current stimulation (tDCS), for a patient who experienced chronic deficits due to PAL (see History below).

tDCS

tDCS uses a low intensity electrical current, delivered via scalp electrodes, to modulate the excitability of brain tissue under and between the electrodes (Bikson et al., 2004). “Traditional” tDCS passes the electricity between two relatively large pads (e.g., 25–35cm²) – an anode that introduces the current and a cathode that collects it. The current study used High Definition (HD-)tDCS, which provides more focal stimulation delivery by surrounding a small center electrode with multiple small electrodes of the opposite polarity. This center electrode uses the full current strength (e.g., 2mA) while the ring electrodes each use about ¼ of the current (e.g., ~0.5mA if 4 electrodes). The neurophysiological effects of HD-tDCS appear to exceed those of the pad-based approach (Kuo et al., 2013; Pelletier & Cicchetti, 2015).

The specific mechanisms through which tDCS exerts effects are still being uncovered but the basic premise is that the subthreshold stimulation modulates the cell membrane thereby altering the probability of neuronal transmission (Stagg & Nitsche, 2011). Effects depend on the polarity of the current (anode vs. cathode), magnitude and duration of current (Samani et al., 2019), and type and orientation of the cell (Rahman et al., 2013; Pelletier & Cicchetti, 2015). Other work suggests tDCS-induced changes along synaptic pathways (Rahman et al., 2013), which may correspond with evidence of altered neurotransmitter levels (Clark et al., 2011; Das et al, 2016; Kim et al., 2014). Evidence of neurophysiologic change outside of the motor system has been provided by altered resting state functional connectivity (Krishnamurthy et al., 2016; Polania et al., 2011; Polania et al., 2012) and task-based (Hampstead, Brown, Hartley, 2014) functional magnetic resonance imaging (fMRI). Given that PAL markedly affects white matter, it is relevant to note that homogenous isotopic white matter conductivity is typically modeled as lower then grey matter, while with anisotropic white matter can be modeled with a directional conductivity higher than grey matter (Suh et al, 2012). Notwithstanding open questions about tissue conductivity values, and specifically how to model anisotropy based on imaging ( Shahid et al., 2014), it is expected that white matter will differently impact overall brain current flow patterns. tDCS has been shown to impact axon terminals (Bikson et al., 2004), but it remains to be understood if and how tDCS would impact axons of passage (Chakraborty et al., 2018; Rahman et al., 2017). Such questions are beyond the scope of the current case study but broach important questions for the larger field.

tDCS has been used in a variety of populations for cognitive enhancement purposes, though we are not aware of any prior use in those with PAL or other anoxic injuries (aside from ischemic stroke). However, literature from related conditions appears promising. For example, a study of 9 patients with leukoaraiosis (ischemic white matter lesions) found that a single session of tDCS (2 mA for 15 minutes with the anode over the primary motor cortex and cathode over inion) in combination with gait and balance training improved both skills compared to balance training alone (Kaski et al., 2013). Likewise, studies in patients who suffered a stroke have demonstrated improved motor (Lindenberg et al., 2010) and language abilities regardless of whether tDCS was applied alone (Boggio et al., 2007) or in combination with therapy (Lindenberg et al., 2010). Specifically, past work with traditional stroke populations which investigated the use of tDCS over the left lateral prefrontal cortex has demonstrated overall improved language fluency (Polanowska et al., 2013; Richardson, et al., 2015; Wang et al., 2019), verbal learning (Yun, Chun, & Kim, 2015), and working memory (Jo et al., 2009). However, some studies have found a lack of cognitive improvement with tDCS in those suffering from traditional stroke (Shaker et al., 2018). Meta-analyses on both motor and language functioning and learning in stroke patients are generally positive (O’Brien et al., 2018; Otal et al., 2015), but some suggest small or non-statistically significant differences between active tDCS protocols and sham (Tedesco Triccas et al., 2016) or poor quality of evidence for tDCS (Elsner et al., 2016a). Conversely, there is also work that suggests no cognitive benefit after multiple tDCS sessions (Elsner et al., 2016a; Valiengo et al., 2017), though studies do not always require the presence of cognitive deficits at the time of enrollment; a limitation that renders change highly unlikely. Thus, a great deal more work is needed in this area to determine optimal dosing and targeting parameters. Such exploration is entirely feasible since tDCS is widely regarded as well tolerated and safe, including when multiple sessions are provided (Bikson et al., 2016; Brunoni et al., 2011; Paneri et al., 2016; Reckow et al., 2018).

As described below, our patient with PAL demonstrated significant cognitive and functional deficits even after exhausting other treatment options. Therefore, we investigated the use of HD-tDCS over the left lateral prefrontal cortex (PFC) for an extended treatment period of 29 sessions at 2mA for 20 minutes conducted over 6 consecutive weeks. No concurrent treatment was provided during this time. Effects were evaluated using a multi-method approach that included neuropsychological testing, informant report, and resting-state fMRI.

Case Study History

The current case (PT1) was a 62-year-old, married, right-handed, White male who, at the age of 57, sustained PAL following an accidental opioid drug overdose. He was found unresponsive the morning after taking the medication and was twice resuscitated before being transported to the hospital. PT1 was intubated in the ER. After two weeks in a medically induced coma he appeared to be recovering well for approximately four days. Consistent with the onset of PAL, he suddenly decompensated while still hospitalized on day four and remained on inpatient and rehabilitation units for the next four months. Neuroimaging (MRI) during this time noted extensive, symmetric, and diffuse periventricular and deep white matter hyperintensities as well as significant volume loss.

PT1 presented for neuropsychological evaluation at an outpatient clinic about five years after the anoxic event, at which point he required 24-hour supervision despite completing extensive courses of occupational, physical, and speech therapy. Per informant (wife) report, anterograde memory (from the time of the event) was significantly impaired while retrograde memory was relatively intact. PT1 was independent in activities of daily living (ADLs) but was generally dependent for most instrumental ADLs. He helped with some household chores as long as frequent prompts about when and how to perform the activities were provided. In this regard, he demonstrated problems with procedural knowledge (e.g., recalling and correctly sequencing the steps associated with making coffee). Speech was reportedly limited the first two years after the event but gradually improved and was characterized primarily by language issues such as short, halting phrases and a general sense of pressured production. A self-report questionnaire completed by his wife indicated that PT1 demonstrated significant executive dysfunction compared to before his anoxic event including reduced inhibitory control (e.g. frequent swearing, inappropriate social comments) that appeared to interact with the other cognitive changes and resulted in social isolation for PT1 and, to some extent, his wife. There was no history of learning or attentional disorders and he was reportedly an above average student. He earned a bachelor’s degree and subsequent legal degree and was a successful attorney for over 20 years at the time of the event. His previous medical history included non-Hodgkin’s Lymphoma (treated with chemotherapy 13 years prior to the neuropsychological evaluation). He had a history of alcohol dependence but had been sober for about 20 years at the time of the evaluation. Medications included Celexa, Ritalin (5mg), aspirin (81mg), fish oil, and a daily multivitamin. These medications had been stable for several months prior to participation and his spouse reported consistent, daily use for all medications throughout the entire study protocol. There were no reported medication changes during the study period.

Neuropsychological testing revealed marked and pervasive cognitive impairment. PT1 had intact simple attentional abilities, but at least mildly impaired sustained attention, working memory, and processing speed. Visuoperception was variably impaired, but visuoconstruction was intact. Speech was hypophonic and pressured with intact articulation. He was noticeably disinhibited as he frequently interrupted test instructions and initiated tasks prior to instructions being completed. Similar to his wife’s report, he tended to provide an initial “burst” of responding during testing and would then state “that’s it,” though prompting from the examiner typically elicited additional responding. His verbal fluency was mild (phonemic) to moderately (semantic) impaired. Confrontation naming and repetition were intact. Anterograde learning and memory were moderately to severely impaired regardless of modality (i.e., verbal vs. visuospatial). PT1 had mild difficulty identifying solution strategies when confronted with a novel problem solving task, and his overall performance was severely impaired on the measure, largely due to severe perseveration. His ability to shift between two concurrent lines of thought was severely impaired. A formal measure of inhibitory control was mildly impaired.

MRI findings at the time of testing revealed interval worsening as reflected by global atrophy as well as hyperintensities throughout the supratentorial white matter. Such structural changes are consonant with previous findings of progressive damage in the years following PAL (Shprecher & Mehta, 2010).

Methods

Procedures

Overview (Table 1):

Table 1.

Outline of Procedures

Pre-Studyy (~6 months before treatment)	Baseline Session 1 (T-4 weeks)	Baseline Session 2 (T-2 weeks)	HD-tDCS Sessions (29 separate days)	Post-Treatment Session	Follow-Up Session (10-weeks post-treatment)
Initial clinical evaluation	fMRI	fMRI	HD-tDCS (2mA for 20 minutes)	fMRI	fMRI
	Neuropsych testing  RBANS1  BADS2  COWAT3  Trails A & B4	Questionnaires  FrsBe6  ADLQ7	Safety Questionnaire	Neuropsych testing  RBANS  BADS  COWAT  Trails A & B	Neuropsych testing  RBANS  BADS  COWAT  Trails A & B
	Questionnaires  GDS5			Questionnaires  GDS  FrsBe  ADLQ	Questionnaires  GDS  FrsBe  ADLQ

¹Repeatable Battery for Assessment of Neuropsychological Status (RBANS) (Randolph, 1998)

²Behavioral Assessment of Dysexecutive Syndrome (BADS) (Wilson, Alderman, Burgess, Emslie, & Evans, 1996)

³Controlled Oral Word Association Test (COWAT) (Benton, Hamsher, & Sivan, 1994)

⁴Trail Making A & B (TMT) (Reitan, 1958)

⁵Geriatric Depression Scale, (GDS) (Yesavage et al. 1983)

⁶Frontal Systems Behavior Scale (FrsBe) (Locasio, Growdon, & Corkin, 1995)

⁷Activities of Daily Living Questionnaire (ADLQ) (Grace, Stout, & Malloy, 1999).

Given the severity and functional impact of PT1’s objective and subjective deficits in executive functioning (e.g. mental flexibility, planning, inhibition), language (e.g., fluency, pressured speech), and learning and memory, we targeted the left lateral prefrontal cortex (PFC) using HD-tDCS. We evaluated potential neurophysiologic effects using resting state fMRI, neuropsychological testing, and self-/informant-report questionnaires at two time points before (baseline 1 = 4 weeks before; baseline 2 = 1 week before) and two time points after treatment (post-treatment = 1 week after; follow-up session = 10 weeks after). Tolerability and safety were assessed after each daily HD-tDCS session using a standard questionnaire (Brunoni et al., 2011). No randomization or blinding was used given the nature of the study. All procedures were approved by the institutional review board and PT1 and his wife provided written consent.

Neuropsychological Testing, Self-Report, and Informant Report

We performed additional neuropsychological testing at the time of study enrollment since there was ~6 month delay since the previously described clinical evaluation (Table 1). Baseline results (Table 2) were consistent with the previous clinical evaluation and document the persistence and severity of the cognitive deficits.

Table 2.

RCI Scores

	Baseline to Post-testing	Post-testing to Follow-up	Baseline to Follow-up
RBANS
Immediate Memory	0	1.46	1.46
Visuospatial	1.30	−2.00	−0.71
Attention	−0.81	1.14	0.34
Language	1.95	−2.43	−0.49
Delayed Memory	2.43	−1.46	0.97

fMRI

Anatomical and resting state images were collected through a GE MR750 3T magnetic resonance system (GE, Milwaukee, WI) with a 32-channel phased array head coil. Sequence parameters for anatomical acquisition were: Field of view (FOV) = 256, Matrix = 256 × 256, 156 slices per volume, 1 × 1 × 1 mm voxel size, TR = 12 ms, TE = 5 ms, TI = 500 ms, flip angle = 15°. For functional resting state data, PT1 was instructed to focus his gaze on a fixation cross (i.e., eyes open) on the screen and not to fall asleep. Resting state data were acquired through a multiband echo planar imaging (EPI) sequence with parameters: FOV = 240, Matrix = 74 × 74, 45 slices per volume, 3.24 × 3.24 × 3 mm voxel size, TR = 900 ms, TE = 30 ms, flip angle = 70°. We acquired 512 volumes but dropped the first 6 to allow for signal normalization, resulting in a total of 7’35.4” of resting state data.

Both anatomical and functional images were preprocessed and analyzed through SPM8 (SPM8; Wellcome Trust Centre for Neuroimaging). Anatomical images were spatially normalized to a standard MNI template using the voxel-based morphometry toolbox (VBM8 http://dbm.neuro.uni-jena.de/vbm) and DARTEL high-dimensional warping and resampled to a 3×3×3 mm voxel size. Slice timing correction was applied for functional volumes. Functional volumes were then realigned to the first volume to correct for head motion and further co-registered with the high-resolution sagittal images. Estimated deformation fields from normalization were applied to normalize functional images to MNI space and smoothed with a 5-mm FWHM Gaussian kernel. Time course data for each voxel was band-pass filtered (0.01 to 0.10 Hz band) to capture the low-frequency spontaneous BOLD oscillations. Translational and rotational motion data were added as motion regressors as well with their first derivative and quadratic terms to regress out motion artifacts from all voxels. White matter and CSF signals were also regressed out with the PCA CompCor method (Behzadai et al., 2007). Global signal regression was not used.

Resting state functional connectivity was examined using the 264 node parcellation atlas defined by Power et al. (2013). We included 8 additional nodes in the hippocampus and amygdala (bilaterally) using the Automated Anatomical Labeling (AAL) atlas as reference (2 nodes in left and right amygdala; 6 nodes in hippocampus – 1 in the each of the left and right head, body, and tail). We created 5 mm spheres at these 272 nodes and extracted time course data over all volumes and Pearson product–moment correlation coefficients were calculated between the average BOLD time course in the 272 node regions. Correlation coefficients were then transformed to z scores using a Fisher r to z transformation. Graph theory metrics, including nodal strength, were calculated through the ‘igraph’ package in R. We accepted Power’s (2013) network designation for each node and extracted graph metrics for use during subsequent data analysis. We selected the six cognitive networks most relevant to this case, which included the dorsal attention, ventral attention, salience, cingulo-opercular, frontoparietal, default mode networks.

HD-tDCS Methods

PT1 underwent 29 HD-tDCS sessions, administered once a day, on consecutive weekdays, over a six-week period (with an exception of his final week which was once a day for four days). Each stimulation session consisted of 30 second “ramp up” and “ramp down” periods with 19 minutes of intervening stimulation at 2mA that was performed using a Soterix Medical Inc. tES unit with attached 4×1 unit. The 4×1 unit passively splits the current among the 4 ring electrodes. The center HD electrode was placed at F5 (anode) while the surrounding cathodes were placed at F9, Fp1, F1, and C5 of the 10–20 International Positioning System. We selected F5 as the cite for the anode since this montage targeted both ventro- and dorso-lateral prefrontal cortices, which was deemed appropriate given his diffuse difficulty with multiple aspects of executive functioning (especially cognitive control). Each set of five electrodes were used for 10 sessions and the location of each electrode was rotated to where any given electrode was used as the center anode twice and ring cathode 8 times. The resulting finite element model (created with the ROAST platform; Huang et al., 2019) indicates this montage effectively targeted the left lateral PFC (see Figure 1). Before each session, PT1 completed a questionnaire that included medication use, hours of sleep, alcohol and recreational drug use (there were none reported), all of which were constant throughout the 29 sessions. Once these electrode locations were measured, elastic head netting (Surgilast®) was placed on his head and HD electrode holders were fitted through the mesh at the appropriate locations. Holders were filled with approximately 10ml of conductive gel. Impedance was checked at each electrode site using the “quality unit” measurement provided by the Soterix Medical Inc. 4×1 unit prior to the start of stimulation each day. Values above 1.0 were rare but were checked to ensure there were no confounding factors (e.g., hair, air bubbles). A ten-minute saturation period was given between electrode placement and start of stimulation to further reduce impedance, after which stimulation began. PT1 sat quietly in a room with the examiner during tDCS sessions. PT1 also completed a side effects questionnaire (Brunoni et al., 2011) that was administered before and immediately after stimulation (as recommended by Reckow et al., 2018).

Figure 1.

Finite element model of electric current flow on PT1 brain based on ROAST. Center anode at F5, ring cathodes at F9, Fp1, F1, C5.

Results

Tolerability of HD-tDCS

HD-tDCS was well tolerated as PT1 reported only mild tingling (79% of sessions), mild itching (72%), and mild burning sensation (39%). Other symptoms (e.g. scalp pain, neck pain) occurred during two or fewer sessions. On the morning of the 21st session (a Monday morning), red spots were noted across his forehead, including at the location of the FP1 electrode. These spots were determined as unlikely associated with HD-tDCS since they were not present at the end of the previous session and were also evident on the right side of his forehead (where no stimulation was performed). His wife speculated that these spots were from wearing an old (unwashed) hat for several days in a row. In an abundance of caution, the FP1 electrode was moved approximately 1 cm anteriorly for 5 sessions to avoid the irritated skin. No further redness was noted. No unexpected or severe adverse effects occurred. Thus, tolerability and safety were high across these 29 sessions.

Changes in Neuropsychological Performance

As noted above, PT1 demonstrated persistent deficits across baseline evaluations. However, reliable change indices (calculated by subtracting the baseline from post test score and then dividing by the standard error of the known test-retest difference; a value > 1.96 was considered significant) demonstrated improvement on the RBANS Delayed Memory Index (RCI = 2.47) and Visuospatial Index (RCI = 1.98) (see Table 2). Likewise, semantic fluency performance improved by over 1.5 SD during post-treatment. Performances returned to baseline levels at follow-up (see Table 3). Thus, there is an inverse “V”-shaped curve with improvements demonstrated immediately after the 29 HD-tDCS sessions but regression to baseline after 10 weeks of no treatment.

Table 3.

Neuropsychological Testing, Self-Report, and Informant-Report Questionnaire Results at Baseline, Post-testing, and Follow-up Sessions.

	Baseline	Post-testing	Follow-up
ATTENTION
Trailmaking Test Part A	0.67	0.67	−2.5
Trailmaking Test Part B	DC	DC	DC
RBANS
Digit Span	−1.05	−1.05	−0.57
Coding	−1.66	−2.42	−1.78
Attention Index	−1.4	−1.75	−1.25
VISUOSPATIAL SKILLS
RBANS
Figure Copy	−5.94	−4.18	−4.76
Line Orientation	0.14	0.83	−0.55
Visuospatial Index	−1.75	−1.25	−2.33
LANGUAGE
COWAT	−1.5	−1.85	−1.5
RBANS
Naming	0.6	0.6	0.6
Fluency	−2.17	−0.22	−3.04
Language Index	−1.3	−0.25	−1.5
LEARNING AND MEMORY
RBANS
List Learning	−1.78	−1.78	−1.11
Story Learning	−3.26	−3.83	−2.97
Immediate Memory Index	−2.75	−2.75	−2.1
List Recall	−2.27	−1.36	−2.27
List Recognition	−6.17	−4.5	−2.83
Story Recall	−3.95	−3	−4.42
Figure Recall	−2.9	−1.65	−2.65
Delayed Memory Index	<−3.00	−2.67	<−3.00
EXECUTIVE FUNCTION
BADS
Rule Shift*	3	4	4
Act Plan*	3	4	2
Key Search*	1	1	1
Temp Judgment*	0	1	0
Zoo Map*	0	0	0
Total	<−3.00	−2.67	<−3.00
SELF-REPORT/ INFORMANT REPORT
GDS	0	0	1
FrSBe*
Self-before	98	56	106
Self-after	101	134	137
Wife-before	54	51	53
Wife-after	153	121	119
Caregiver-after	120	113	101
ADLQ*(all raw scores)
Self- Self care	0	11.11	5.56
Self- House care	33.33	20	38.89
Self- Employ./Recreation	33.33	0	33.33
Self- Shopping/Money	44.44	33.33	33.33
Self- Travel	33.33	11.11	33.33
Self- Communication	20	13.33	20
Wife- Self care	33.33	16.67	16.67
Wife- House care	83.33	61.11	55.56
Wife- Employ./Recreation	66.67	44.44	58.33
Wife- Shopping/Money	66.67	55.56	55.56
Wife- Travel	91.67	83.33	55.56
Wife- Communication	53.33	33.34	26.67
Caregiver- Self care	11.11	16.67	11.11
Caregiver- House care	77.78	77.78	72.22
Caregiver- Employ./Recreation	55.56	44.44	66.67
Caregiver- Shopping/Money	55.56	55.56	55.56
Caregiver- Travel	75	75	91.67
Caregiver- Communication	41.67	33.33	6.67

Note: Z-Scores unless otherwise stated

^*= Raw Scores; DC = Discontinued; FrSBe and ADLQ listed as Baseline session were given during Baseline session 2.

Self- and Informant-Report

Self-report measures suggested enhanced insight into deficits at both post-treatment sessions relative to baseline. Specifically, PT1’s baseline responding on the FrSBe was characterized by nominal endorsement of executive dysfunction either before or after the event (i.e., claiming no effect of PAL). In contrast, his post-treatment reports indicate nominal dysfunction prior to PAL but high levels of dysfunction following the injury. In fact, his post-treatment report of impairment was more comparable to that of his wife’s and caregiver’s baseline ratings. Informants reported improved executive functioning post-treatment. Similarly, he reported significant levels of impairment on the Activities of Daily Living Questionnaire (ADLQ) pre-treatment whereas he reported lower levels, at post-testing, consistent with the relative improvement both his wife and caregiver reported on this measure at post-treatment.

Although he remained dependent overall, qualitative reports from his wife and caregiver described him as showing greater empathy and social appropriateness with less impulsivity and pressured speech. Per his wife’s report, PT1 began independently planning and completing household chores, was better able to follow commands, and showed improved memory (e.g., remembering events, requests, conversations) within the first two weeks of HD-tDCS treatment. By the end of HD-tDCS treatment sessions, he successfully began texting (with complete sentences) and using a computer tablet independently – neither of which he had been able to do despite months of practice with his wife and caregiver. Both informants felt these improvements generally persisted at follow-up (see Table 3).

Changes in resting-state fMRI

Given the case-study nature of this report, we focused on changes in the six major networks (i.e., dorsal attention, ventral attention, salience, cingulo-opercular, frontoparietal, default mode) using a raw threshold correlation value of 0.1. We examined connectivity strength (i.e., r-value of each connection for each node within a network) at baseline (using the mean values of baseline 1 and baseline 2) relative to post-treatment and the follow-up scans (see Figure 2 and Table 4). An inverse “V” emerged where network strength increased post training but returned to (or below) baseline at the 10-week follow-up in both the dorsal attention and cingulo-opercular networks. The ventral attention network showed the opposite pattern with reduced network strength at post-training and a return to baseline at follow-up. Nominal changes were evident in the other networks.

Figure 2.

Changes in resting-state fMRI

Table 4.

Means and Standard Errors for resting-state fMRI

Network	Baseline Mean (SE)	Post-Testing Mean (SE)	Follow-up Mean (SE)
Cingulo-Opercular	15.19(0.73)	17.80(0.85)	13.21(0.82)
Fronto-Parietal	23.57(0.75)	23.10(1.02)	23.13(0.97)
Default Mode	20.91(0.65)	20.31(0.61)	22.86(0.96)
Salience	17.24(1.18)	15.89(1.50)	15.76(1.81)
Dorsal Attention	21.85(0.69)	26.37(1.58)	19.39(1.02)
Ventral Attention	21.89(0.52)	20.05(1.23)	20.91(1.26)

Note: Baseline raw scores are averaged between baseline session 1 and 2.

Discussion

The current study is the first of our knowledge to investigate the use of HD-tDCS in a case of PAL with significant cognitive and daily life dysfunction. PT1 demonstrated improvement from baseline to post-testing on delayed memory performance, visuospatial skills, and verbal fluency. These improvements coincide with increased dorsal attention and cingulo-opercular network connectivity from baseline to post-testing, whereas ventral attention network connectivity decreased. PT1’s insight improved during his treatment sessions, and his wife and caregiver reported improved daily functioning, including better empathy, social appropriateness, and speech production. However, while self and informant report noted sustained improvement, cognitive test performance did not sustain at the 10-week follow-up.

Given the multi-year persistence of baseline deficits, pattern of improvement, and general regression to (or below) baseline, this case appears to add to the growing literature that HD-tDCS can have positive benefits. The sustained period of treatment is presumably central to these gains and PT1’s improvement is grossly similar to past work in large vessel stroke (Boggio et al., 2007; Lindenberg et al., 2010; Polanowska et al., 2013). The overall pattern of cognitive and neurophysiologic changes are all biologically plausible given the left lateral PFC focus, as this region is a convergence zone for aspects of attention, executive control, language, and learning/memory (Siddiqui et al., 2008). We cannot say with any certainty that 2 mA for 20 minutes or that 29 sessions are optimal dosage parameters, however, there is a general paucity of treatment parameters at this time and prior work has suggested the need for a more thorough consideration of individual differences (Esmaeilpour et al., 2017). In that respect, our individual computational model suggested a maximum electric field of about 0.5 V/m (with most current in the 0.3–0.4 range), but it is unclear whether this is optimal or whether higher (or lower) electric field would be more effective (see Esmaeilpour et al., 2017).

Relatedly, resting state fMRI findings demonstrated increased network strength at post-testing, specifically in dorsal attention and cingulo-opercular networks. The left lateral prefrontal cortex is involved in both of these networks (Dosenbach et al., 2008; Vossel et al., 2014), again supporting the biological plausibility of HD-tDCS effects. Further, as both of these networks are related to arousal, attention (specifically object oriented attention), and processing speed (Corbetta et al., 2008; Sadaghiani & D’Esposito, 2015), their increase in strength may help explain the observed cognitive improvement. The lack of findings in other networks (e.g. salience, fronto-parietal) and initial reduction in the ventral attention network also support the specificity of the effects, especially given past findings that the ventral attention system can be suppressed when the dorsal network is engaged (Corbetta et al., 2008).

The fact that nearly all changes regressed to baseline by the 10-week follow-up further supports the effects of HD-tDCS. Past work has been mixed in terms of the persistence of post-tDCS change (Elsner et al., 2016b; Pisegna et al., 2016; Elsner et al., 2019; Polanowska et al., 2013) so it appears that sustained HD-tDCS or booster sessions are needed to maintain effects. We note such effects are not unique to HD-tDCS as many medications for chronic conditions require ongoing use to be effective, and we advocate that HD-tDCS and other forms of neuromodulation be considered in a similar manner.

As mentioned, our 29 day session protocol is consistent with other multi-session studies (Boggio et al., 2007; Yang et al., 2012), and past work suggests that more sessions appear to provide additional benefit with no additional side effects (Nikolin et al., 2018). There is little evidence that small breaks in protocol, such as over weekends in PT1’s protocol, is detrimental to overall cognitive or behavioral effects. In fact, one study found greater working memory improvement between sessions that were separated by a two-day weekend than those separated by 24 hours (Au et al., 2016). Further, breaks spanning 24 hours to two weeks showed no change in outcomes or effect sizes in a previous meta-analysis (Dedoncker et al., 2016).

Limitations of the current study include those associated with a single case study; however, the rarity of PAL and associated mortality rates render large-scale studies unlikely. Likewise, far more work is needed to establish dose-response data across populations (e.g., Thair et al., 2017), which is the focus of our (BMH) ongoing triple blind RCT (NCT03875326). While we focused on the effects of HD-tDCS in isolation, it is entirely possible that combined non-pharmacologic (e.g., cognitive training + HD-tDCS) or pharmacologic (e.g., medication + HD-tDCS) approaches may be particularly effective, as suggested by the concept of functional targeting (Bikson et al., 2013) and prior evidence of pharmacologic enhancement (Batsikadze, et al., 2013; Kuo et al., 2016). Further, use of reliable alternative forms may be helpful in future studies in order to minimize stimulus specific practice effects. With these caveats in mind, our current findings provide some initial evidence supporting the benefits of HD-tDCS in a population lacking therapeutic options.