As the primary input nucleus of the sensorimotor cortico-basal ganglia loop (19), the DLS of the basal ganglia contributes to motor learning and execution (20–24). Associated with stimulus-response learning, the DLS is believed to be a primary substrate for the development of automaticity associated with implicit, procedural learning, particularly sequencing, critical for the fluid execution of complex motor actions [reviewed in Ref. (25)]. M1 exhibits intrinsic activity-dependent synaptic plasticity, important for motor skill and sequence learning (26). This activity is shaped by both intracortical afferents and basal ganglia efferents (27).

The basal ganglia are comprised of GABAergic medium spiny neurons (MSNs) of the striatonigral (direct) and striatopallidal (indirect) projections. These striatal projections modulate inhibition of cortical activity through the output nuclei of the basal ganglia that provide tonic inhibition of excitatory thalamocortical projections (17, 18). In turn, cortical glutamatergic afferents on striatal MSNs can activate the striatonigral or striatopallidal pathways, disinhibiting or inhibiting cortical activity, respectively [(28, 29); Figure 1A]. The responsiveness of striatonigral and striatopallidal MSNs to specific cortical synaptic inputs can be modulated through synaptic strength (Figure 1B). Increased synaptic strength is commonly defined by the emergence of long-term potentiation (LTP) and decreased synaptic strength by long-term depression (LTD). For example, a specific cortical synaptic input may be potentiated (LTP) at striatonigral disinhibitory MSNs while a cortical synaptic input on striatopallidal inhibitory MSNs is depressed (LTD), leading to the combined facilitation of cortical activity (30–34). Increasing evidence supports bidirectional plasticity at corticostriatal synapses (35–41), suggesting the opposite pattern can arise as well. For example, a specific cortical synaptic input might be potentiated, increasing striatopallidal MSN activity in response to that input and increasing cortical inhibition. The basal ganglia, through selective synaptic potentiation and depression, facilitate particular cortical activities while inhibiting others, thus filtering cortical activity through cortico-basal ganglia-thalamo-cortical loops. While the precise function of this filter remains subject to debate, it is hypothesized that the purpose of this basal ganglia filter is to select one action and suppress others (29, 42). An alternative view is that the basal ganglia, by selectively facilitating productive, task-relevant cortical activity and suppressing non-productive and/or irrelevant activity, optimizes cortical processing to increase speed and efficiency.

Increasing evidence suggest that reduced dopamine may shift corticostriatal plasticity in striatopallidal synapses favoring LTP rather than LTD, inverting plasticity such that conditions that would normally yield LTD produce LTP instead (38–41). The net effect of this would be that everywhere a cortical afferent should be disinhibited it would, instead, be further inhibited. Such a shift or inversion in the directional control of plasticity – the aberrant learning hypothesis – would transform an optimizing substrate into an “anti-optimizing” one that impedes rather than facilitates responding (25, 41, 46–48). Aberrant learning, then, transforms the basal ganglia that normally functions to filter and facilitate cortical activity into a disruptive filter that impedes motor activity.

Aberrant learning arising from reduced striatal dopamine contributes significantly to impaired motor performance over and above the direct motor effects of diminished dopamine (41, 48). The correction of aberrant learning and abnormal corticostriatal plasticity may represent an important component of L-DOPA treatment in PD and underlie the poorly understood long-duration response (LDR), where the benefits of dopamine replacement on motor performance persists beyond the pharmacokinetic half life of L-DOPA (25, 41, 48–50). Given the number of potential modulators of synaptic plasticity within the striatum, that include but are not limited to adenosine, glutamatergic and cholinergic neurotransmission, decreasing inappropriate potentiation at corticostriatal synapses in the striatopallidal pathway may serve as an important therapeutic target for facilitating motor learning and recovery of function in PD. For example, correction of aberrant learning may be an important therapeutic mechanism of adenosine antagonists (36, 41).

The aberrant learning hypothesis can be understood as an extension of the classic model of PD where there is an imbalance between the direct and indirect pathways (28, 29, 51–53). With aberrant learning, this imbalance is structurally encoded as inappropriate synaptic strengths [i.e., inverted corticostriatal plasticity; (25, 41, 46–48, 54)]. Thus, even if dopamine is restored, the inappropriate learning that has already been established will continue to degrade motor performance until appropriate synaptic plasticity and learning has replaced the inappropriate (41). Conversely, if dopamine is reduced (e.g., discontinuation of L-DOPA), performance will initially be partially protected as the appropriate synaptic strengths will facilitate corticostriatal throughput; however, as aberrant plasticity and learning return, synaptic structure will again become inverted and anti-optimal and initially retained function will deteriorate (48).

Learning is the encoding of information through alterations in synaptic strengths that underlie memory formation and skill acquisition. Though the cortex and striatum both exhibit learning and synaptic plasticity, how learning in each substrate affects learning in the other is poorly understood.

Reduction in cortical activity in cortical regions that participate in the dorsal striatal sensorimotor loop (e.g., M1, PMC, posterior parietal) as well as reduced activity in regions associated with the cognitive loop (e.g., DLPFC) have been well documented in PD (6, 56). Reduced cortical activity in these regions is consistent with the classic model of an imbalance between the direct and indirect pathway that results in increased inhibitory tone on cortical activity. However, numerous studies have observed increased activity in these same regions associated with task performance (8–13, 15, 16, 57–62). While task-related increases in cortical activity may be construed as compensatory, it may reflect reduced processing efficiency. With the acquisition of automaticity, healthy normal controls exhibit decreased cortical activity while PD subjects do not show such reductions, consistent with increased cortical load arising from dysfunction in corticostriatal circuits (58). Such increased cortical activity may arise from the loss of appropriate corticostriatal filtering. In a recent study, Ng et al. (57) have shown spatially greater cortical activation (i.e., more spread out) in unmedicated PD subjects performing a simple motor task compared to healthy controls; this spatially greater activation is normalized by L-DOPA, which the authors characterize as a “focusing effect.” In the view adopted here, the increased cortical activity could reflect both compensatory cortical circuits and pathophysiology in the basal ganglia filter. First, denervation in the DLS induces greater inhibitory tone, diminishing cortical activity, which in turn leads to compensatory functional connectivity that increases intracortical and cerebellar drive on cortical activity. Second, this increased activity lacks the filter that “focuses” cortical activity, resulting in overall greater, less efficient cortical activation. The net result is that the cortex has to work harder to maintain behavior and does so with less efficiency.

As functional connectivity shifts to drive cortical activity and maintain behavior, cortical mechanisms of activity-dependent synaptic plasticity continue to facilitate learning to refine and calibrate cortical networks and ensembles to adapt to new patterns of afferent inputs. In effect, the cortex has to learn the adaptations. If the filtering or “focusing” effect of the DLS and the sensorimotor basal ganglia loop were merely absent, learning might simply be slower and less efficient. From the perspective of the aberrant learning hypothesis, however, the problem is more insidious. Dopamine denervation induces inverted corticostriatal plasticity in the striatopallidal pathway that actively inhibits precisely those high activity cortical afferents that should be facilitated, providing an anti-optimizing filter. Instead of increasing signal-to-noise ratio – enhancing productive and diminishing non-productive/irrelevant cortical activity – aberrant learning would actively diminish signal. Thus, as activity-dependent cortical learning adjust cortical synaptic strengths to improve performance and adapt to shifted functional connectivity, the resulting changes in cortical activity are subsequently opposed by aberrant learning in the DLS effectively filtering out such learning by inappropriately inhibiting precisely those activities the cortex has just learned to enhance. It is not difficult to imagine a progression where inappropriate filtering in conjunction with continued aberrant learning leads to further compensatory cortical activity that is less efficient and, in turn, also degraded by aberrant learning resulting in a vicious cycle of increasingly greater but less efficient cortical activity to maintain motor function.

Aberrant corticostriatal plasticity, from the perspective of the aberrant learning hypothesis, represents more than a simple loss of function. Rather, it is an active, insidious process that hijacks corticostriatal plasticity, not only impeding the role of the basal ganglia as an effective filter of cortical activity, but structurally encoding inappropriate learning as synaptic strengths that can actively disrupt cortical function. Such aberrant learning will gradually unravel and invert a lifetime of learning – and the millions of finely calibrated synaptic strengths that support that learning – accelerating functional deterioration associated with neurodegeneration.

As dopamine denervation progresses, cortical compensatory activity is engaged. The reciprocal relationship between cortical and basal ganglia structures, however, suggests that aberrant corticostriatal plasticity may increase the burden placed on the cortex while simultaneously interfering with its compensatory capacity. If true, this means that therapeutic agents that ameliorate aberrant learning would have the additional advantage of supporting cortical compensation. In particular, decreasing an inappropriate, “anti-optimizing” basal ganglia filter may facilitate improved cortical learning and adaptation. Therapeutic strategies specifically targeted at correcting or blocking aberrant learning may slow functional deterioration associated with neurodegeneration as well as support adaptive, compensatory mechanisms, providing a form of disease-modifying neuroprotection that may mitigate the functional decline associated with disease progression. Thus, targeting subcellular signaling pathways and cellular mechanisms specific to striatopallidal synaptic plasticity to either diminish inappropriate LTP or enhance appropriate LTD may offer an avenue for the development of alternative disease-modifying, neuroprotective therapeutics (25, 41, 50).

An important aspect of aberrant learning is that it introduces a delay between the pathophysiology (or its correction) and the resulting functional effects on behavior. That is, aberrant learning that occurs now will affect performance in the future. Conversely, improvement associated with corrected aberrant learning will be observed gradually over time as restored corticostriatal plasticity relearns and recalibrates synapses. It is precisely this delay in observing the effects of corrected aberrant learning that we have proposed underlies the LDR to L-DOPA (25, 48). If aberrant corticostriatal plasticity degrades cortical learning, a delay might be expected in the correction of impaired cortical functions as the cortex also undergoes relearning. Interestingly, it has been observed that several cognitive symptoms of PD do not appear to be improved with L-DOPA administration [e.g., Ref. (63)]. Why this might be is unclear, but one possibility is that cognitive symptoms associated with cortical functions may, at least partially, arise from impaired cortical learning induced by aberrant corticostriatal plasticity. If so, L-DOPA would not immediately correct previously degraded or inappropriate cortical learning; however, similar to the LDR, such symptoms might improve gradually over time as cortical learning is protected from the deleterious effects of aberrant corticostriatal plasticity. Conversely, Kishore et al. (64, 65) have recently observed a deficit in plasticity in M1 in newly diagnosed, untreated patients that is corrected under optimal medication (absent fluctuations or dyskinesia). This corrected plasticity is sustained even during the OFF state, suggesting it may represent a LDR (64). The degree to which these findings relate to dopamine replacement and a potential LDR action directly in M1 versus arising secondary to the correction of aberrant corticostriatal plasticity and its effects on cortical processing and learning remain to be determined.

This hypothesis has potentially significant implication for rehabilitative treatments in PD. Rehabilitation fundamentally involves repetition, i.e., practice, and is premised on mechanisms of learning and plasticity. If those underlying mechanisms are not only impaired, but potentially induce counter-productive, aberrant learning and plasticity, the efficacy of rehabilitation could be compromised. Rehabilitative strategies might be most beneficial, then, when conducted under optimal medication to maximally support cortical compensatory learning. The success of physical therapy programs, including programs which patients practice independently (eg., Big and Loud), may be contingent on training and practice being performed during the ON medication state.

In conclusion, agents that target and ameliorate aberrant corticostriatal plasticity in the striatopallidal pathway may represent an important avenue for the development of new therapeutics, potentially yielding a protective LDR-like treatment independent of dopamine replacement with its attendant complications. Remediating an insidious process of inappropriate corticostriatal synaptic plasticity may mitigate circuit deterioration and support cortical compensatory mechanisms, modifying the rate and severity of functional decline associated with disease progression. Further research on aberrant learning and its potential effects on cortical function and learning are needed and may yield new insights and treatment strategies.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.